Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture

ABSTRACT

Glucopyranosyl-substituted benzonitrile derivatives defined according to claim  1 , including the tautomers, the stereoisomers thereof, the mixtures thereof and the salts thereof. The compounds according to the invention are suitable for the treatment of metabolic disorders.

This application claims priority benefit from EP 06 113 412, filed May3, 2006; EP 06 124 833, filed Nov. 27, 2006; and PCT/EP2007/051411,filed Feb. 14, 2007, all of which are incorporated herein in theirentirety.

The present invention relates to glucopyranosyl-substituted benzonitrilederivatives of the general formula I

wherein the group R³ is defined hereinafter, including the tautomers,the stereoisomers, the mixtures thereof and the salts thereof. Theinvention further relates to pharmaceutical compositions containing acompound of formula I according to the invention as well as the use of acompound according to the invention for preparing a pharmaceuticalcomposition for the treatment of metabolic disorders. In addition, theinvention relates to processes for preparing a pharmaceuticalcomposition as well as a compound according to the invention.

In the literature, compounds which have an inhibitory effect on thesodium-dependent glucose cotransporter SGLT2 are proposed for thetreatment of diseases, particularly diabetes.

Glucopyranosyl-substituted aromatic groups and the preparation thereofand their possible activity as SGLT2 inhibitors are known from theinternational application WO 2005/092877 and the publications citedtherein.

AIM OF THE INVENTION

The aim of the present invention is to find newglucopyranosyl-substituted benzonitrile derivatives, particularly thosewhich are active with regard to the sodium-dependent glucosecotransporter SGLT, particularly SGLT2. A further aim of the presentinvention is to discover glucopyranosyl-substituted benzene derivativeswhich have an enhanced inhibitory effect on the sodium-dependent glucosecotransporter SGLT2 in vitro and/or in vivo compared with known,structurally similar compounds and/or have better pharmacological orpharmacokinetic properties.

A further aim of the present invention is to provide new pharmaceuticalcompositions which are suitable for the prevention and/or treatment ofmetabolic disorders, particularly diabetes.

Other aims of the present invention will become apparent to the skilledman directly from the foregoing and following remarks.

OBJECT OF THE INVENTION

In a first aspect the present invention relates toglucopyranosyl-substituted benzonitrile derivatives of formula I

wherein

-   R³ denotes hydrogen, fluorine, chlorine, bromine, iodine, methyl,    ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl,    3-methyl-but-1-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl,    1-hydroxy-cyclohexyl, difluoromethyl, trifluoromethyl,    pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl,    2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl,    1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,    2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl,    2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy,    2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl,    methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl or    cyano,-   or a derivative thereof wherein one or more hydroxyl groups of the    β-D-glucopyranosyl group are acylated with groups selected from    (C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, phenylcarbonyl and    phenyl-(C₁₋₃-alkyl)-carbonyl;-   including tautomers, stereoisomers thereof or mixtures thereof; and    physiologically acceptable salts thereof.

The compounds according to the invention and the physiologicallyacceptable salts thereof have valuable pharmacological properties,particularly an inhibitory effect on the sodium-dependent glucosecotransporter SGLT, particularly SGLT2. Moreover compounds according tothe invention may have an inhibitory effect on the sodium-dependentglucose cotransporter SGLT1. Compared with a possible inhibitory effecton SGLT1 the compounds according to the invention preferably inhibitSGLT2 selectively.

The present invention also relates to the physiologically acceptablesalts of the compounds according to the invention with inorganic ororganic acids.

This invention also relates to pharmaceutical compositions, containingat least one compound according to the invention or a physiologicallyacceptable salt according to the invention, optionally together with oneor more inert carriers and/or diluents.

This invention also relates to the use of at least one compoundaccording to the invention or a physiologically acceptable salt thereoffor preparing a pharmaceutical composition which is suitable for thetreatment or prevention of diseases or conditions which can beinfluenced by inhibiting the sodium-dependent glucose cotransporterSGLT, particularly SGLT2.

This invention also relates to the use of at least one compoundaccording to the invention or a physiologically acceptable salt thereoffor preparing a pharmaceutical composition which is suitable for thetreatment of one or more metabolic disorders.

In a further aspect the present invention relates to the use of at leastone compound according to the invention or one of the physiologicallyacceptable salts thereof for preparing a pharmaceutical composition forpreventing the degeneration of pancreatic beta cells and/or forimproving and/or restoring the functionality of pancreatic beta cells.

In a further aspect the present invention relates to a use of at leastone compound according to the invention or one of the physiologicallyacceptable salts thereof for preparing a pharmaceutical composition forpreventing, slowing, delaying or treating diseases or conditionsattributed to an abnormal accumulation of liver fat in a patient in needthereof.

This invention also relates to the use of at least one compoundaccording to the invention or a physiologically acceptable salt thereoffor preparing a pharmaceutical composition for inhibiting thesodium-dependent glucose cotransporter SGLT, particularly SGLT2.

The invention further relates to a process for preparing apharmaceutical composition according to the invention, characterised inthat a compound according to the invention or one of the physiologicallyacceptable salts thereof is incorporated in one or more inert carriersand/or diluents by a non-chemical method.

The present invention also relates to a process for preparing thecompounds of general formula I according to the invention, characterisedin that

a) in order to prepare compounds of general formula I which are definedas hereinbefore and hereinafter,

a compound of general formula II

wherein

-   R′ denotes H, C₁₋₄-alkyl, (C₁₋₁₈-alkyl)carbonyl,    (C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl and    aryl-(C₁₋₃-alkyl)-carbonyl, wherein the alkyl or aryl groups may be    mono- or polysubstituted by halogen;-   R^(8a), R^(8b),-   R^(8c), R^(8d) independently of one another denote hydrogen or an    allyl group, a benzyl group, a (C₁₋₄-alkyl)carbonyl,    (C₁₋₄-alkyl)oxycarbonyl, arylcarbonyl, aryl-(C₁₋₃-alkyl)-carbonyl    and aryl-(C₁₋₃-alkyl)-oxycarbonyl or a R^(a)R^(b)R^(c)Si group or a    ketal or acetal group, particularly an alkylidene or arylalkylidene    ketal or acetal group, while in each case two adjacent groups    R^(8a), R^(8b), R^(8c), R^(8d) may form a cyclic ketal or acetal    group or a 1,2-di(C₁₋₃-alkoxy)-1,2-di(C₁₋₃-alkyl)-ethylene bridge,    while the above-mentioned ethylene bridge forms, together with two    oxygen atoms and the two associated carbon atoms of the pyranose    ring, a substituted dioxane ring, particularly a    2,3-dimethyl-2,3-di(C₁₋₃-alkoxy)-1,4-dioxane ring, and while alkyl,    allyl, aryl and/or benzyl groups may be mono- or polysubstituted by    halogen or C₁₋₃-alkoxy, and while benzyl groups may also be    substituted by a di-(C₁₋₃-alkyl)amino group; and-   R^(a), R^(b), R^(c) independently of one another denote C₁₋₄-alkyl,    aryl or aryl-C₁₋₃-alkyl, wherein the aryl or alkyl groups may be    mono- or polysubstituted by halogen;-   while by the aryl groups mentioned in the definition of the above    groups are meant phenyl or naphthyl groups, preferably phenyl    groups;-   and wherein the group R³ is defined as hereinbefore and hereinafter;-   is reacted with a reducing agent in the presence of a Lewis or    Brønsted acid, while any protective groups present are cleaved    simultaneously or subsequently; or    b) in order to prepare compounds of general formula I,    a compound of general formula III

wherein R^(8a), R^(8b), R^(8c), R^(8d) and R³ are defined ashereinbefore and hereinafter, with the proviso that at least onesubstituent selected from R^(8a), R^(8b), R^(c), R^(8d) is not hydrogen;

-   the protective groups R^(8a), R^(8b), R^(8c), R^(8d) not being    hydrogen are cleaved; and-   if desired a compound of general formula I thus obtained is    converted by acylation into a corresponding acyl compound of general    formula I, and/or-   if necessary any protective group used in the reactions described    above is cleaved and/or-   if desired a compound of general formula I thus obtained is resolved    into its stereoisomers and/or-   if desired a compound of general formula I thus obtained is    converted into the salts thereof, particularly for pharmaceutical    use into the physiologically acceptable salts thereof.

A further aspect of the present invention relates to novel intermediatesas described in the reaction schemes and in the experimental parthereinafter.

DETAILED DESCRIPTION OF THE INVENTION

The aspects according to the present invention, in particular thecompounds, pharmaceutical compositions and uses thereof, refer toglucopyranosyl-substituted benzonitrile derivatives of general formula Ias defined hereinbefore and hereinafter, or derivatives thereof,including tautomers, stereoisomers or mixtures thereof, andphysiologically acceptable salts thereof.

In the following alternative preferred embodiments of the presentinvention are described:

According to a first embodiment of the present invention R³ denoteshydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl,trifluoromethyl, pentafluoroethyl,_(—)2-hydroxyl-ethyl, hydroxymethyl,3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl,3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl,2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl,2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy,2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl,ethylsulfinyl, ethylsulfonyl, trimethylsilyl or cyano.

According to a second embodiment of the present invention R³ denoteshydrogen, fluorine, chlorine, bromine, iodine, hydroxy,difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy,methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl,ethylsulfonyl, trimethylsilyl or cyano.

According to a third embodiment of the present invention R³ denotesmethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl,tert-butyl, 3-methyl-but-1-yl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, difluoromethyl, trifluoromethyl, pentafluoroethyl,2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl,2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl,1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl or2-ethoxy-ethyl.

According to a fourth embodiment of the present invention R³ denotesmethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl,tert-butyl, 3-methyl-but-1-yl, difluoromethyl, trifluoromethyl orpentafluoroethyl.

According to a fifth embodiment of the present invention R³ denotescyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

According to a sixth embodiment of the present invention R³ denotes1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl or1-hydroxy-cyclohexyl.

According to a seventh embodiment of the present invention R³ denotes2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl,2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl,1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl or2-ethoxy-ethyl.

According to an eighth embodiment of the present invention R³ denotes2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl or1-hydroxy-1-methyl-ethyl.

According to a ninth embodiment of the present invention R³ denoteshydroxy, difluoromethyloxy, trifluoromethyloxy or cyano.

According to a tenth embodiment of the present invention R³ denotesmethyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl orpentafluoroethyl.

Preferably all hydroxyl groups of the β-D-glucopyranosyl group areunsubstituted or only the hydroxyl group O-6 of the β-D-glucopyranosylgroup is substituted as defined. Preferred substituents are selectedfrom among (C₁₋₈-alkyl)carbonyl, (C₁₋₈-alkyl)oxycarbonyl andphenylcarbonyl. Even more preferred substituents are selected from amongacetyl, methoxycarbonyl and ethoxycarbonyl, in particular acetyl andethoxycarbonyl.

The nomenclature in structural formulas used above and hereinafter, inwhich a bond of a substituent of a cyclic group, as e.g. a phenyl ring,is shown towards the centre of the cyclic group, denotes, unlessotherwise stated, that this substituent may be bound to any freeposition of the cyclic group bearing an H atom.

The compounds according to the invention may be obtained using methodsof synthesis known in principle. Preferably the compounds are obtainedby the following methods according to the invention which are describedin more detail hereinafter.

The glucose derivatives of formula II according to the invention may besynthesised from D-gluconolactone or a derivative thereof by adding thedesired benzylbenzene compound in the form of an organometallic compound(Scheme 1).

The reaction according to Scheme 1 is preferably carried out startingfrom a halogenated benzylbenzene compound of general formula IV, whereinHal denotes chlorine, bromine, or iodine. R¹ in Scheme 1 denotes cyanoor a group that may be subsequently converted to a cyano group such aschlorine, bromine, carboxy, carboxylic ester, carboxamide or aderivative thereof, a boron or silyl group, a protected or maskedaldehyde function such as e.g. acetal or thiazole, or a protected ormasked amino functionality such as e.g. nitro. The Grignard or lithiumreagent of benzylbenzene (V) may be prepared from the correspondingchlorinated, brominated or iodinated benzylbenzene IV either via aso-called halogen-metal exchange reaction or by inserting the metal intothe carbon-halogen bond. The halogen-metal exchange to synthesize thecorresponding lithium compound V may be carried out for example with anorganolithium compound such as e.g. n-, sec- or tert-butyllithium. Theanalogous magnesium compound may also be generated by a halogen-metalexchange with a suitable Grignard reagent such as e.g. isopropyl- orsec-butylmagnesium bromide or chloride or diisopropyl- ordi-sec-butylmagnesium without or in the presence of an additional saltsuch as e.g. lithium chloride that may accelerate the metalationprocess; the specific transmetalating organomagnesium compound may alsobe generated in situ from suitable precursors (see e.g. Angew. Chem.2004, 116, 3396-3399 and Angew. Chem. 2006, 118, 165-169 and referencesquoted therein). In addition, ate complexes of organomagnesium compoundsresulting from combining e.g. butylmagnesium chloride or bromide orisopropylmagnesium chloride or bromide and butyllithium, may be employedas well (see e.g. Angew. Chem. 2000, 112, 2594-2596 and TetrahedronLett. 2001, 42, 4841-4844 and references quoted therein). Thehalogen-metal exchange reactions are preferably carried out between 40°C. and −100° C., particularly preferably between 10° C. and −80° C., inan inert solvent or mixtures thereof, such as for example diethylether,dioxane, tetrahydrofuran, toluene, hexane, dimethylsulfoxide,dichloromethane or mixtures thereof. The magnesium or lithiumderivatized compounds thus obtained may optionally be transmetalatedwith metal salts such as e.g. cerium trichloride, zinc chloride orbromide, indium chloride or bromide, to form alternative organometalcompounds (V) suitable for addition. Alternatively, the organometalcompound V may also be prepared by inserting a metal into thecarbon-halogen bond of the haloaromatic compound IV. Lithium ormagnesium are suitable elemental metals for this transformation. Theinsertion can be achieved in solvents such as e.g. diethylether,dioxane, tetrahydrofuran, toluene, hexane, dimethylsulfoxide andmixtures thereof at temperatures ranging from −80 to 100° C., preferablyat −70 to 40° C. In cases in which no spontaneous reaction takes placeprior activation of the metal might be necessary such as e.g. treatmentwith 1,2-dibromoethane, iodine, trimethylsilylchloride, acetic acid,hydrochloric acid and/or sonication. The addition of the organometalcompound V to gluconolactone or derivatives thereof (VI) is preferablycarried out at temperatures between 40° C. and −100° C., particularlypreferably at 0 to −80° C., in an inert solvent or mixtures thereof, toobtain the compound of formula II. All foregoing reactions may beperformed in air though execution under inert gas atmosphere such asargon and nitrogen is preferred. The metalation and/or coupling reactionmay also be carried out in microreactors and/or micromixers which enablehigh exchange rates; for example analogously to the processes describedin WO 2004/076470. Suitable solvents for the addition of the metalatedphenyl group V to the appropriately protected gluconolactone VI are e.g.diethylether, dimethoxyethane, benzene, toluene, methylene chloride,hexane, tetrahydrofuran, dioxane, N-methylpyrrolidone and mixturesthereof. The addition reactions may be carried out without any furtheradjuvants or in the case of sluggishly reacting coupling partners in thepresence of a promoter such as e.g. BF₃*OEt₂ or Me₃SiCl (see M.Schlosser, Organometallics in Synthesis, John Wiley & Sons,Chichester/New York/Brisbane/Toronto/Singapore, 1994). Preferreddefinitions of the substituents R⁸ in Scheme 1 are benzyl, substitutedbenzyl, allyl, trialkylsilyl, particularly preferably trimethylsilyl,triisopropylsilyl, allyl, 4-methoxybenzyl and benzyl. If two adjacentsubstituents R⁸ are linked together, these two substituents arepreferably part of a benzylideneacetal, 4-methoxybenzylideneacetal,isopropylketal or constitute a dioxane with 2,3-dimethoxy-butylene whichis linked via the 2 and 3 positions of the butane with the adjacentoxygen atoms of the pyranose. The group R′ preferably denotes hydrogen,C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl or C₁₋₄-alkyloxycarbonyl, particularlypreferably hydrogen, methyl or ethyl. The group R′ is introduced afterthe addition of the organometallic compound V or a derivative thereof tothe gluconolactone VI. If R′ equals hydrogen or C₁₋₄-alkyl the reactionsolution is treated with an alcohol such as e.g. methanol or ethanol orwater in the presence of an acid such as e.g. acetic acid,methanesulfonic acid, toluenesulfonic acid, sulfuric acid,trifluoroacetic acid, or hydrochloric acid. R′ may also be attachedafter preparation of the hydrogen compound II by reacting the anomerichydroxyl group with a suitable electrophile such as e.g. methyl iodide,dimethyl sulfate, ethyl iodide, diethyl sulfate, acetyl chloride, oracetic anhydride in the presence of a base such as e.g. triethlyamine,ethyldiisopropylamine, sodium or potassium or cesium carbonate, sodiumor potassium or cesium hydroxide. The hydroxyl group can also bedeprotonated prior to the addition of the electrophile with e.g. sodiumhydride. During installing R′ the protective groups R⁸ may be cleaved iflabile under the reaction conditions employed resulting in thecorresponding protonated compound, i.e. compound II in which R⁸ equalsH.

The synthesis of haloaromatic compound of formula IV may be carried outusing standard transformations in organic chemistry or at least methodsknown from the specialist literature in organic synthesis (see interalia J. March, Advanced Organic Reactions, Reactions, Mechanisms, andStructure, 4th Edition, John Wiley & Sons, Chichester/NewYork/Brisbane/Toronto/Singapore, 1992 and literature cited therein).More specifically, the use of transition metals and organo metalcompounds for the synthesis of aromatic compounds has been detailed indifferent monographs (see e.g. L. Brandsma, S. F. Vasilevsky, H. D.Verkruijsse, Application of Transition Metal Catalysts in OrganicSynthesis, Springer-Verlag, Berlin/Heidelberg, 1998; M. Schlosser,Organometallics in Synthesis, John Wiley & Sons, Chichester/NewYork/Brisbane/Toronto/Singapore, 1994; P. J. Stang, F. Diederich,Metal-Catalyzed Cross-Coupling Reactions, Wiley-VCH, Weinheim, 1997 andreferences quoted therein). The synthesis strategies described in thefollowing provide a demonstration of this, by way of example. Inaddition, the aglycon part may also be assembled with the pyranosemoiety already present using the same synthetic approaches.

Scheme 2 shows the preparation of a precursor compound that may servefor the synthesis of the haloaromatic compound of formula IV startingfrom a benzoylchloride and a second aromatic group applyingFriedel-Crafts acylation conditions or variations thereof. R¹ in Scheme2 denotes cyano or a group that may be subsequently converted to a cyanogroup such as chlorine, bromine, carboxy, carboxylic ester, carboxamideor a derivative thereof, a protected or masked aldehyde function such ase.g. thioacetal or thiazole, or a protected or masked aminofunctionality such as e.g. nitro. This classic reaction has a widesubstrate scope and is commonly carried out in the presence of acatalyst which is used in catalytic or stoichiometric amounts, such ase.g. AlCl₃, FeCl₃, iodine, iron, ZnCl₂, sulphuric acid, ortrifluoromethanesulphonic acid. Instead of the benzoyl chloride thecorresponding carboxylic acid, anhydride, ester or benzonitrile may beused as well. The reactions are preferentially carried out inchlorinated hydrocarbons such as e.g. dichloromethane and1,2-dichloroethane at temperatures from −30 to 120° C., preferably at 30to 100° C. However, solvent-free reactions or reactions in a microwaveoven are also possible.

In Scheme 3 the substituent R denotes C₁₋₃-alkyl or aryl and R¹ cyano ora group that may be subsequently converted to a cyano group such aschlorine, bromine, carboxy, carboxylic ester, carboxamide or aderivative thereof, a boron or silyl group, a protected or maskedaldehyde function such as e.g. acetal or thiazole, or a protected ormasked amino function such as e.g. nitro. Starting from the diarylketoneor diarylmethanol the diarylmethane is accessible in one or two reactionsteps. The diarylketone may be reduced to the diarylmethane in two stepsvia the corresponding diphenylmethanol or in one step. In the two-stepvariant the ketone is reduced with a reducing agent such as for examplea metal hydride such as e.g. NaBH₄, LiAlH₄ or iBu₂AlH to form thealcohol. The resulting alcohol can be converted in the presence of aLewis acid such as for example BF₃*OEt₂, InCl₃ or AlCl₃ or Brønsted acidsuch as for example hydrochloric acid, sulfuric acid, trifluoroaceticacid, or acetic acid with a reducing agent such as e.g. Et₃SiH, NaBH₄,or Ph₂SiClH to the desired diphenylmethane. The one-step processstarting from the ketone to obtain the diphenylmethane may be carriedout e.g. with a silane such as e.g. Et₃SiH, a borohydride such as e.g.NaBH₄ or an aluminum hydride such as LiAlH₄ in the presence of a Lewisor Brønsted acid such as for example BF₃*OEt₂,tris(pentafluorophenyl)borane, trifluoroacetic acid, hydrochloric acid,aluminum chloride or InCl₃. The reactions are preferably carried out insolvents such as e.g. halogenated hydrocarbons such as dichloromethane,toluene, acetonitrile, or mixtures thereof at temperatures of −30 to150° C., preferably at 20 to 100° C. Reductions with hydrogen in thepresence of a transition metal catalyst such as e.g. Pd on charcoal areanother possible method of synthesis. Reductions according toWolff-Kishner or variants thereof are also possible. The ketone isfirstly converted with hydrazine or a derivative thereof, such as e.g.1,2-bis(tert-butyldimethylsilyl)hydrazine, into the hydrazone whichbreaks down under strongly basic reaction conditions and heating to formthe diphenylmethane and nitrogen. The reaction may be carried out in onereaction step or after isolation of the hydrazone or a derivativethereof in two separate reaction steps. Suitable bases include e.g. KOH,NaOH or KOtBu in solvents such as e.g. ethyleneglycol, toluene, DMSO,2-(2-butoxyethoxy)ethanol or tert-butanol; solvent-free reactions arealso possible. The reactions may be carried out at temperatures between20 to 250° C., preferably between 80 to 200° C. An alternative to thebasic conditions of the Wolff-Kishner reduction is the Clemmensenreduction which takes place under acidic conditions, which may also beused here. The alcohol function in diarylmethanol may also first betransformed into a better leaving group such as e.g. chloride, bromide,iodide, acetate, carbonate, phosphate, or sulfate; the subsequentreduction step to form the diarylmethane is widely described in theorganic chemistry literature.

In Scheme 4 R¹ denotes cyano or a group that may be subsequentlyconverted to a cyano group such as chlorine, bromine, carboxy,carboxylic ester, carboxamide or a derivative thereof, a boron or silylgroup, a protected or masked aldehyde function such as e.g. acetal orthiazole, or a protected or masked amino function such as e.g. nitro.The term “Alk” denotes C₁₋₄-alkyl and each substituent R isindependently selected from each other from the group consisting of H,C₁₋₃-alkyl and C₁₋₃-alkoxy. Scheme 4 delineates the synthesis ofdiarylmethanes and possible precursor compounds thereof starting from ametalated phenyl group. Lithium or magnesium substituted aromaticcompounds may be synthesized from chlorinated, brominated, or iodinatedaromatics by a halogen-metal exchange reaction with

e.g. butyllithium, isopropylmagnesium halogenide, or diispropylmagnesiumor by insertion of the elemental metal into the halogen-carbon bond. Thecorresponding boron substituted compound such as e.g. boronic acid,boronic acid ester, or dialkylarylborane, is accessible from thesemetalated phenyl groups by reaction with a boron electrophile such ase.g. boronic acid ester or a derivative thereof. In addition, theborylated aromatic compound may also be prepared from the correspondinghalogenated or pseudohalogenated precursor and a diboron or boranecompound through a transition metal, e.g. palladium, catalyzed reaction(see e.g. Tetrahedron Lett. 2003, p. 4895-4898 and references quotedtherein). The lithium or magnesium substituted phenyl compounds add tobenzaldehydes (step 3) and benzoic acids or derivatives thereof (step 4)such as benzoic acid esters, benzamides such as e.g. of the Weinrebtype, benzonitriles, or benzoyl chlorides. These reactions mayprincipally be conducted without an additional transition metal catalystor transmetalation to another metal such as e.g. cerium, indium or zinc;sometimes the use of one of the latter alternatives is advantageous.Aryl boronic acids can be added to benzaldehydes by means of a rhodiumcatalyst furnishing the respective diarylmethanol (see e.g. Adv. Synth.Catal. 2001, p. 343-350 and references quoted therein). Moreover,arylboronic acids, esters thereof, dialkylarylboranes, oraryltrifluoroborates may be coupled with benzoyl chlorides mediated by atransition metal such as e.g. palladium, a complex or a salt thereofdelivering diarylketones. Metalated phenyl groups can be reacted withbenzyl electrophiles such as benzyl chlorides, bromides, or iodidesaffording diarylmethanes. Lithium or magnesium derivatized phenylcompounds are reacted favorably but not always necessarily in thepresence of a transition metal such as e.g. copper, iron, or palladium(see e.g. Org. Lett. 2001, 3, 2871-2874 and references quoted therein).Transmetallation from lithium or magnesium to e.g. boron, tin, silicon,or zinc furnishes e.g. the corresponding aromatic boronic acids,stannanes, silanes or zinc compounds, respectively, that may undergocoupling with benzyl electrophiles, e.g. benzyl halogenides, carbonates,phosphates, sulfonates, or carboxylic esters. The reaction is conductedin the presence of a transition metal, e.g. palladium, nickel, rhodium,copper, or iron (see e.g. Tetrahedron Lett. 2004, p. 8225-8228 and Org.Lett. 2005, p. 4875-4878 and references cited therein).

Scheme 5 displays possible pathways to attach the cyano residue to thecentral phenyl group at various stages of the synthesis of the targetmolecules. The cyano group may be introduced via a transition metalmediated coupling reaction of an appropriate cyano source such as e.g.sodium, potassium, zinc or copper cyanide with a halogenated orpseudohalogenated phenyl group. Suitable catalysts may be derived fromtransition metals such as e.g. palladium, rhodium, nickel, iron orcopper that may be used in elemental form such as e.g. palladium oncarbon, as salts such as e.g. palladium chloride, bromide or acetate orcomplexes with e.g. phosphines such as e.g. triphenylphosphine,tri-tert-butylphosphine or dppf or alkenes such as e.g.dibenzylideneacetone. The active catalyst may be generated in situ orprior to the addition to the reaction mixture. Additives such as e.g.zinc as element or salt may be advantageous (see Tetrahedron Lett. 2005,46, 1849-1853 and Tetrahedron Lett. 2005, 46, 1815-1818 and referencesquoted therein). Reacting the corresponding zinc, magnesium or lithiumcompound, accessible from the chlorinated, brominated or iodinatedcompound via a halogen metal exchange reaction or by insertion of therespective metal into the halogen bond, with a cyano electrophile suchas e.g. p-tolylsulfonyl cyanide, cyanogen bromide or 2-pyridyl cyanateis another viable approach to install the cyano functionality (see e.g.Synth. Commun. 1996, 3709-3714 and references quoted therein).

An alternative introduction of the cyano group is the synthesis startingfrom aldehyde or carboxamide (Scheme 6). The aldehydic function itselfcan be introduced as such, protected, or masked. Popular protectivegroups for the aldehyde function are acetals, but other protectivegroups may be used as well (see T. W. Greene, P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, Inc., New York, 1999).Suitable masks for the aldehyde function are e.g. olefins and thiazoles.The aldehyde may be converted to the cyano function using e.g.hydroxylamine in combination with e.g. formic acid, concentratedhydrochloric acid, polyphosphoric acid or pyridine-toluene. Theintermediate oxime formed under these reaction conditions may beisolated before dehydration to deliver the final product. Alternativehydroxylamine reagents such as e.g. bistrifluoroacetylhydroxylamine andNH₂OSO₃ may be used as well and afford the nitrile without additionalreagents. Further reagents applicable are e.g. NH₄PO₄H₂ and nitropropanein acetic acid, trimethylsilyl azide or S,S-dimethylsulfurdiimide.

Carboxamides may be suitable nitrile precursors, too. The conversion maybe carried out with dehydrating agents such as e.g. trifluoroacetic acidanhydride, phosphorous pentoxide, POCl₃, CCl₄-phosphine combination,Cl₃COCl-amine combination, Burgess reagent, Vilsmeyer reagent, SOCl₂, orcyanuric chloride. Starting from the corresponding monoalkylatedcarboxamide, carboxylic acid, ester or carboxylic chloride the formationof the nitrile is also doable in one pot without the isolation of anyintermediate.

A well established approach to introduce the nitrile function is theso-called Sandmeyer reaction with copper cyanide and the correspondingdiazonium compound accessible via diazotization of the respectiveaniline derivative. The synthesis of diazonium compounds and theirsubsequent cyano-de-diazoniation has extensively been documented in theorganic chemistry literature.

An alternative approach for the construction of the Diarylmethane Unitis shown in Scheme 8. It makes use of an ortho fluoro substitutedbenzonitrile which is either commercially available or can be obtainedby methods mentioned before. The ortho fluoro substituted benzonitrileis reacted with an alkyl phenylacetate substituted by R³ under basicconditions (see e.g. J. Org. Chem. 55, 1990, 4817-4821; J. Heterocycl.Chem., 32, 1995, 1461-1466) followed by ester cleavage anddecarboxylation (see e.g. J. Heterocycl. Chem., 32, 1995, 1461-1466;Org. Prep. Proced. Int. 37, 2005, 550-555) or directde-alkoxycarbonylation (see e.g. J. Med. Chem. 46, 2003, 5249-5257;Angew. Chem. Int. Ed. 47, 2004, 6493-6496).

In order to prepare compounds of general formula I, in process a)according to the invention, a compound of general formula II

wherein R¹ and R³ are as hereinbefore defined and

-   R^(8a), R^(8b), R^(8c), R^(8d) are as hereinbefore defined and    independently of one another represent for example acetyl, pivaloyl,    benzoyl, tert-butoxycarbonyl, benzyloxycarbonyl, allyl,    trialkylsilyl, benzyl or substituted benzyl or in each case two    adjacent groups R^(8a), R^(8b), R^(8c), R^(8d) form a    benzylideneacetal or isopropylideneketal or a 2,3-dimethoxy-butylene    group which is linked via position 2 and 3 of the butylene group to    the oxygen atoms of the pyranose ring and forms with them a    substituted dioxane,-   which may be obtained as hereinbefore described, is reacted with a    reducing agent in the presence of a Lewis or Brønsted acid.

Suitable reducing agents for the reaction include for example silanes,such as triethyl-, tripropyl-, triisopropyl- or diphenylsilane, sodiumborohydride, sodium cyanoborohydride, zinc borohydride, boranes, lithiumaluminium hydride, diisobutylaluminium hydride or samarium iodide. Thereductions are carried out without or in the presence of a suitableBrønsted acid, such as e.g. hydrochloric acid, toluenesulphonic acid,trifluoroacetic acid or acetic acid, or Lewis acid, such as e.g. borontrifluoride etherate, trimethylsilyltriflate, titaniium tetrachloride,tin tetrachloride, scandium triflate or zinc iodide. Depending on thereducing agent and the acid the reaction may be carried out in asolvent, such as for example methylene chloride, chloroform,acetonitrile, toluene, hexane, diethyl ether, tetrahydrofuran, dioxane,ethanol, water or mixtures thereof at temperatures between −60° C. and120° C. One particularly suitable combination of reagents consists forexample of triethylsilane and boron trifluoride etherate, which isconveniently used in acetonitrile or dichloromethane at temperatures of−60° C. and 60° C. Moreover, hydrogen may be used in the presence of atransition metal catalyst, such as e.g. palladium on charcoal or Raneynickel, in solvents such as tetrahydrofuran, ethyl acetate, methanol,ethanol, water or acetic acid, for the transformation described.

Alternatively, in order to prepare compounds of general formula Iaccording to process b) according to the invention, in a compound ofgeneral formula III

wherein R³ is as hereinbefore defined and

-   R^(8a) to R^(8d) denote one of the protective groups defined    hereinbefore, such as e.g. an acyl, arylmethyl, allyl, acetal, ketal    or silyl group, and which may be obtained for example by reduction    from the compound of formula II as hereinbefore described, the    protective groups are cleaved.

It is understood that one or several of the groups R^(8a) to R^(8d) maybe changed during the aforementioned synthetic processes.

Any acyl protecting group used is cleaved for example hydrolytically inan aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water,tetrahydrofuran/water or dioxane/water, in the presence of an acid suchas trifluoroacetic acid, hydrochloric acid or sulphuric acid or in thepresence of an alkali metal base such as lithium hydroxide, sodiumhydroxide or potassium hydroxide or aprotically, e.g. in the presence ofiodotrimethylsilane, at temperatures between 0 and 120° C., preferablyat temperatures between 10 and 100° C. A trifluoroacetyl group ispreferably cleaved by treating with an acid such as hydrochloric acid,optionally in the presence of a solvent such as acetic acid attemperatures between 50 and 120° C. or by treating with sodium hydroxidesolution optionally in the presence of a solvent such as tetrahydrofuranor methanol at temperatures between 0 and 50° C.

Any acetal or ketal protecting group used is cleaved for examplehydrolytically in an aqueous solvent, e.g. in water, isopropanol/water,acetic acid/water, tetrahydrofuran/water or dioxane/water, in thepresence of an acid such as trifluoroacetic acid, hydrochloric acid orsulphuric acid or aprotically, e.g. in the presence ofiodotrimethylsilane, at temperatures between 0 and 120° C., preferablyat temperatures between 10 and 100° C.

A trimethylsilyl group is cleaved for example in water, an aqueoussolvent mixture or a lower alcohol such as methanol or ethanol in thepresence of a base such as lithium hydroxide, sodium hydroxide,potassium carbonate or sodium methoxide.

In aqueous or alcoholic solvents, acids such as e.g. hydrochloric acid,trifluoroacetic acid or acetic acid are also suitable. For cleaving inorganic solvents, such as for example diethyl ether, tetrahydrofuran ordichloromethane, it is also suitable to use fluoride reagents, such ase.g. tetrabutylammonium fluoride.

A benzyl, methoxybenzyl or benzyloxycarbonyl group is advantageouslycleaved hydrogenolytically, e.g. with hydrogen in the presence of acatalyst such as palladium/charcoal in a suitable solvent such asmethanol, ethanol, ethyl acetate or glacial acetic acid, optionally withthe addition of an acid such as hydrochloric acid at temperaturesbetween 0 and 100° C., but preferably at ambient temperatures between 20and 60° C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved intrifluoroacetic acid in the presence of anisole.

A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid or hydrochloric acidor by treating with iodotrimethylsilane optionally using a solvent suchas methylene chloride, dioxane, methanol or diethylether.

In the reactions described hereinbefore, any reactive groups presentsuch as ethynyl, hydroxy, amino, alkylamino or imino groups may beprotected during the reaction by conventional protecting groups whichare cleaved again after the reaction.

For example, a protecting group for an ethynyl group may be thetrimethylsilyl or triisopropyl group. The 2-hydroxisoprop-2-yl group mayalso be used as a protective group.

For example, a protecting group for a hydroxy group may be atrimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group.

Protecting groups for an amino, alkylamino or imino group may be, forexample, a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl,tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or2,4-dimethoxybenzyl group.

Moreover, the compounds of general formula I obtained may be resolvedinto their enantiomers and/or diastereomers, as mentioned hereinbefore.Thus, for example, cis/trans mixtures may be resolved into their cis andtrans isomers, and compounds with at least one optically active carbonatom may be separated into their enantiomers.

Thus, for example, the cis/trans mixtures may be resolved bychromatography into the cis and trans isomers thereof, the compounds ofgeneral formula I obtained which occur as racemates may be separated bymethods known per se (cf. Allinger N. L. and Eliel E. L. in “Topics inStereochemistry”, Vol. 6, Wiley Interscience, 1971) into their opticalantipodes and compounds of general formula I with at least 2 asymmetriccarbon atoms may be resolved into their diastereomers on the basis oftheir physical-chemical differences using methods known per se, e.g. bychromatography and/or fractional crystallisation, and, if thesecompounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiralphases or by recrystallisation from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives such as e.g. esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g. on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are e.g. the D- and L-forms of tartaric acid ordibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelicacid, camphorsulphonic acid, glutamic acid, aspartic acid or quinicacid. An optically active alcohol may be for example (+) or (−)-mentholand an optically active acyl group in amides, for example, may be a(+)-or (−)-menthyloxycarbonyl.

Furthermore, the compounds of formula I may be converted into the saltsthereof, particularly for pharmaceutical use into the physiologicallyacceptable salts with inorganic or organic acids. Acids which may beused for this purpose include for example hydrochloric acid, hydrobromicacid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaricacid, succinic acid, lacetic acid, citric acid, tartaric acid or maleicacid.

Moreover, the compounds obtained may be converted into mixtures, forexample 1:1 or 1:2 mixtures with amino acids, particularly withalpha-amino acids such as proline or phenylalanine, which may haveparticularly favourable properties such as a high crystallinity.

The compounds according to the invention are advantageously alsoobtainable using the methods described in the examples that follow,which may also be combined for this purpose with methods known to theskilled man from the literature, for example the methods described in WO98/31697, WO 01/27128, WO 02/083066, WO 03/099836, WO 2004/063209, WO2005/092877 and WO 2006/120208.

The present invention also relates to novel intermediate compounds asdescribed in the reaction schemes hereinbefore and as described in theexperimental section hereinafter.

In particular the following intermediate compounds are an additionalaspect of the present invention:

wherein

-   R^(8a) to R^(8d) are defined as hereinbefore and preferably denote H    or acetyl;-   R′ is defined as hereinbefore and preferably denotes H, methyl or    ethyl;-   Alk denotes C₁₋₄-alkyl, preferably methyl or ethyl;-   R¹ is defined as hereinbefore and preferably denotes Br or CN, most    preferably CN;-   R³ is defined as hereinbefore, for example cyclopropyl or    cyclobutyl, and is preferably selected from the group consisting of    chloro, bromo, methyl, ethyl, n-propyl, i-propyl, cyclopropyl,    cyclobutyl, cyclopentyl, hydroxy, cyano;-   LG denotes a leaving group such as Br, I, —O—(SO₂)—CF₃, preferably    —O—(SO₂)—CF₃;-   U denotes Cl, Br, I, —O—CO—C₁₋₄-alkyl, —O—C(═O)—O—C₁₋₄-alkyl or    —OPO(O—C₁₋₄-alkyl)₂; preferably Br.

As already mentioned, the compounds of general formula I according tothe invention and the physiologically acceptable salts thereof havevaluable pharmacological properties, particularly an inhibitory effecton the sodium-dependent glucose cotransporter SGLT, preferably SGLT2.

The biological properties of the new compounds may be investigated asfollows:

The ability of the substances to inhibit the SGLT-2 activity may bedemonstrated in a test set-up in which a CHO-K₁ cell line (ATCC No.CCL-61) or alternatively a HEK293 cell line (ATCC No. CRL-1573), whichis stably transfected with an expression vector pZeoSV (Invitrogen, EMBLaccession number L36849), which contains the cDNA for the codingsequence of the human sodium glucose cotransporter 2 (Genbank Acc. No.NM_(—)003041) (CHO-hSGLT2 or HEK-hSGLT2). These cell lines transport¹⁴C-labelled alpha-methyl-glucopyranoside (14C-AMG, Amersham) into theinterior of the cell in a sodium-dependent manner.

The SGLT-2 assay is carried out as follows:

CHO-hSGLT2 cells are cultivated in Ham's F12 Medium (BioWhittaker) with10% foetal calf serum and 250 μg/mL Zeocin (Invitrogen), andHEK293-hSGLT2 cells are cultivated in DMEM medium with 10% foetal calfserum and 250 μg/mL Zeocin (Invitrogen). The cells are detached from theculture flasks by washing twice with PBS and subsequently treating withtrypsin/EDTA. After the addition of cell culture medium the cells arecentrifuged, resuspended in culture medium and counted in a Casy cellcounter. 40,000 cells per well are seeded into a white, 96-well platecoated with poly-D-lysine and incubated overnight at 37° C., 5% CO₂. Thecells are washed twice with 250 μl of assay buffer (Hanks Balanced SaltSolution, 137 mM NaCl, 5.4 mM KCl, 2.8 mM CaCl₂, 1.2 mM MgSO₄ and 10 mMHEPES (pH 7.4), 50 μg/mL Gentamycin). 250 μl of assay buffer and 5 μl oftest compound are then added to each well and the plate is incubated forfurther 15 minutes in the incubator. 5 μl of 10% DMSO are used as thenegative control. The reaction is started by adding 5 μl of ¹⁴C-AMG(0.05 μCi) to each well. After 2 hours' incubation at 37° C., 5% CO₂,the cells are washed again with 250 μl of PBS (20° C.) and then lysed bythe addition of 25 μl of 0.1 N NaOH (5 min. at 37° C.). 200 μl ofMicroScint20 (Packard) are added to each well and incubation iscontinued for a further 20 min at 37° C. After this incubation theradioactivity of the ¹⁴C-AMG absorbed is measured in a Topcount(Packard) using a ¹⁴C scintillation program.

To determine the selectivity with respect to human SGLT1 an analogoustest is set up in which the cDNA for hSGLT1 (Genbank Acc. No.NM_(—)000343) instead of hSGLT2 cDNA is expressed in CHO-KL or HEK293cells.

The compounds according to the invention may for example have EC50values below 1000 nM, particularly below 200 nM, most preferably below50 nM.

In view of their ability to inhibit the SGLT activity, the compoundsaccording to the invention and the corresponding pharmaceuticallyacceptable salts thereof are suitable for the treatment and/orpreventative treatment of all those conditions or diseases which may beaffected by the inhibition of the SGLT activity, particularly the SGLT-2activity. Therefore, compounds according to the invention areparticularly suitable for the prevention or treatment of diseases,particularly metabolic disorders, or conditions such as type 1 and type2 diabetes mellitus, complications of diabetes (such as e.g.retinopathy, nephropathy or neuropathies, diabetic foot, ulcers,macroangiopathies), metabolic acidosis or ketosis, reactivehypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulinresistance, metabolic syndrome, dyslipidaemias of different origins,atherosclerosis and related diseases, obesity, high blood pressure,chronic heart failure, edema and hyperuricaemia. These substances arealso suitable for preventing beta-cell degeneration such as e.g.apoptosis or necrosis of pancreatic beta cells. The substances are alsosuitable for improving or restoring the functionality of pancreaticcells, and also of increasing the number and size of pancreatic betacells. The compounds according to the invention may also be used asdiuretics or antihypertensives and are suitable for the prevention andtreatment of acute renal failure.

By the administration of a compound according to the invention anabnormal accumulation of fat in the liver may be reduced or inhibited.Therefore according to another aspect of the present invention there isprovided a method for preventing, slowing, delaying or treating diseasesor conditions attributed to an abnormal accumulation of liver fat in apatient in need thereof characterized in that a compound or apharmaceutical composition according to the present invention isadministered. Diseases or conditions which are attributed to an abnormalaccumulation of liver fat are particularly selected from the groupconsisting of general fatty liver, non-alcoholic fatty liver (NAFL),non-alcoholic steatohepatitis (NASH), hyperalimentation-induced fattyliver, diabetic fatty liver, alcoholic-induced fatty liver or toxicfatty liver.

In particular, the compounds according to the invention, including thephysiologically acceptable salts thereof, are suitable for theprevention or treatment of diabetes, particularly type 1 and type 2diabetes mellitus, and/or diabetic complications.

In addition compounds according to the invention are particularlysuitable for the prevention or treatment of overweight, obesity(including class I, class II and/or class III obesity), visceral obesityand/or abdominal obesity.

The dosage required to achieve the corresponding activity for treatmentor prevention usually depends on the compound which is to beadministered, the patient, the nature and gravity of the illness orcondition and the method and frequency of administration and is for thepatient's doctor to decide. Expediently, the dosage may be from 1 to 100mg, preferably 1 to 30 mg, by intravenous route, and 1 to 1000 mg,preferably 1 to 100 mg, by oral route, in each case administered 1 to 4times a day. For this purpose, the compounds according to the inventionmay be formulated, optionally together with other active substances,together with one or more inert conventional carriers and/or diluents,e.g. with corn starch, lactose, glucose, microcrystalline cellulose,magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid,water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propylene glycol, cetylstearyl alcohol, carboxymethylcelluloseor fatty substances such as hard fat or suitable mixtures thereof, toproduce conventional galenic preparations such as plain or coatedtablets, capsules, powders, suspensions or suppositories.

The compounds according to the invention may also be used in conjunctionwith other active substances, particularly for the treatment and/orprevention of the diseases and conditions mentioned above. Other activesubstances which are suitable for such combinations include for examplethose which potentiate the therapeutic effect of an SGLT antagonistaccording to the invention with respect to one of the indicationsmentioned and/or which allow the dosage of an SGLT antagonist accordingto the invention to be reduced. Therapeutic agents which are suitablefor such a combination include, for example, antidiabetic agents such asmefformin, sulphonylureas (e.g. glibenclamide, tolbutamide,glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g.rosiglitazone, pioglitazone), PPAR-gamma-agonists (e.g. GI 262570) andantagonists, PPAR-gamma/alpha modulators (e.g. KRP 297),alpha-glucosidase inhibitors (e.g. acarbose, voglibose), DPPIVinhibitors (e.g. LAF237, MK-431), alpha2-antagonists, insulin andinsulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or amylin.The list also includes inhibitors of protein tyrosinephosphatase 1,substances that affect deregulated glucose production in the liver, suchas e.g. inhibitors of glucose-6-phosphatase, orfructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptorantagonists and inhibitors of phosphoenol pyruvate carboxykinase,glycogen synthase kinase or pyruvate dehydrokinase, lipid loweringagents such as for example HMG-CoA-reductase inhibitors (e.g.simvastatin, atorvastatin), fibrates (e.g. bezafibrate, fenofibrate),nicotinic acid and the derivatives thereof, PPAR-alpha agonists,PPAR-delta agonists, ACAT inhibitors (e.g. avasimibe) or cholesterolabsorption inhibitors such as, for example, ezetimibe, bile acid-bindingsubstances such as, for example, cholestyramine, inhibitors of ileacbile acid transport, HDL-raising compounds such as CETP inhibitors orABC1 regulators or active substances for treating obesity, such assibutramine or tetrahydrolipostatin, dexfenfluramine, axokine,antagonists of the cannabinoid1 receptor, MCH-1 receptor antagonists,MC4 receptor agonists, NPY5 or NPY2 antagonists or β3-agonists such asSB-418790 or AD-9677 and agonists of the 5HT2c receptor.

Moreover, combinations with drugs for influencing high blood pressure,chronic heart failure or atherosclerosis such as e.g. A-II antagonistsor ACE inhibitors, ECE inhibitors, diuretics, β-blockers,Ca-antagonists, centrally acting antihypertensives, antagonists of thealpha-2-adrenergic receptor, inhibitors of neutral endopeptidase,thrombocyte aggregation inhibitors and others or combinations thereofare suitable. Examples of angiotensin II receptor antagonists arecandesartan cilexetil, potassium losartan, eprosartan mesylate,valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312,olmesartan, medoxomil, tasosartan, KT-3-671, GA-0113, RU-64276,EMD-90423, BR-9701, etc. Angiotensin II receptor antagonists arepreferably used for the treatment or prevention of high blood pressureand complications of diabetes, often combined with a diuretic such ashydrochlorothiazide.

A combination with uric acid synthesis inhibitors or uricosurics issuitable for the treatment or prevention of gout.

A combination with GABA-receptor antagonists, Na-channel blockers,topiramat, protein-kinase C inhibitors, advanced glycation end productinhibitors or aldose reductase inhibitors may be used for the treatmentor prevention of complications of diabetes.

The dosage for the combination partners mentioned above is usefully 1/5of the lowest dose normally recommended up to 1/1 of the normallyrecommended dose.

Therefore, in another aspect, this invention relates to the use of acompound according to the invention or a physiologically acceptable saltof such a compound combined with at least one of the active substancesdescribed above as a combination partner, for preparing a pharmaceuticalcomposition which is suitable for the treatment or prevention ofdiseases or conditions which can be affected by inhibiting thesodium-dependent glucose cotransporter SGLT. These are preferablymetabolic diseases, particularly one of the diseases or conditionslisted above, most particularly diabetes or diabetic complications.

The use of the compound according to the invention, or a physiologicallyacceptable salt thereof, in combination with another active substancemay take place simultaneously or at staggered times, but particularlywithin a short space of time. If they are administered simultaneously,the two active substances are given to the patient together; while ifthey are used at staggered times the two active substances are given tothe patient within a period of less than or equal to 12 hours, butparticularly less than or equal to 6 hours.

Consequently, in another aspect, this invention relates to apharmaceutical composition which comprises a compound according to theinvention or a physiologically acceptable salt of such a compound and atleast one of the active substances described above as combinationpartners, optionally together with one or more inert carriers and/ordiluents.

Thus, for example, a pharmaceutical composition according to theinvention comprises a combination of a compound according to theinvention or a physiologically acceptable salt of such a compound and atleast one angiotensin II receptor antagonist optionally together withone or more inert carriers and/or diluents.

The compound according to the invention, or a physiologically acceptablesalt thereof, and the additional active substance to be combinedtherewith may both be present together in one formulation, for example atablet or capsule, or separately in two identical or differentformulations, for example as a so-called kit-of-parts.

In the foregoing and following text, H atoms of hydroxyl groups are notexplicitly shown in every case in structural formulae. The Examples thatfollow are intended to illustrate the present invention withoutrestricting it. The terms “room temperature” and “ambient temperature”are used interchangeably and denote temperatures of about 20° C. Thefollowing abbreviations are used:

-   DMF dimethylformamide-   NMP N-methyl-2-pyrrolidone-   THF tetrahydrofuran    Preparation of the Starting Compounds:

EXAMPLE I

4-Bromo-3-hydroxymethyl-1-iodo-benzene

Oxalyl chloride (13.0 mL) is added to an ice-cold solution of2-bromo-5-iodo-benzoic acid in CH₂Cl₂ (200 mL). DMF (0.2 mL) is addedand the solution is stirred at room temperature for 6 h. Then, thesolution is concentrated under reduced pressure and the residue isdissolved in THF (100 mL). The resulting solution is cooled in anice-bath and LiBH₄ (3.4 g) is added in portions. The cooling bath isremoved and the mixture is stirred at room temperature for 1 h. Thereaction mixture is diluted with THF and treated with 0.1 M hydrochloricacid. Then, the organic layer is separated and the aqueous layer isextracted with ethyl acetate. The combined organic layers are dried(Na₂SO₄) and the solvent is evaporated under reduced pressure to givethe crude product.

Yield: 47.0 g (99% of theory)

EXAMPLE II

4-Bromo-3-chloromethyl-1-iodo-benzene

Thionyl chloride (13 mL) is added to a suspension of4-bromo-3-hydroxymethyl-1-iodo-benzene (47.0 g) in dichloromethane (100mL) containing DMF (0.1 mL). The mixture is stirred at ambienttemperature for 3 h. Then, the solvent and the excess reagent is removedunder reduced pressure. The residue is triturated with methanol anddried.

Yield: 41.0 g (82% of theory)

EXAMPLE III

4-Bromo-1-iodo-3-phenoxymethyl-benzene

Phenol (13 g) dissolved in 4 M KOH solution (60 mL) is added to4-bromo-3-chloromethyl-1-iodo-benzene (41.0 g) dissolved in acetone (50mL). NaI (0.5 g) is added and the resulting mixture is stirred at 50° C.overnight. Then, water is added and the resulting mixture is extractedwith ethyl acetate. The combined extracts are dried and the solvent isevaporated under reduced pressure. The residue is purified bychromatography on silica gel (cyclohexane/ethyl acetate 19:1).

Yield: 38.0 g (79% of theory)

EXAMPLE IV

(5-Bromo-2-chloro-phenyl)-(4-methoxy-phenyl)-methanone

38.3 mL oxalyl chloride and 0.8 mL dimethylformamide are added to amixture of 100 g 5-bromo-2-chloro-benzoic acid in 500 mLdichloromethane. The reaction mixture is stirred for 14 h, then filteredand separated from all volatile constituents in a rotary evaporator. Theresidue is dissolved in 150 mL dichloromethane, the resultant solutionis cooled to −5° C., and 46.5 g anisole are added. Then 51.5 g aluminumtrichloride are added batchwise so that the temperature does not exceed5° C. The solution is stirred for 1 h at 1 to 5° C. and then poured ontocrushed ice. The organic phase is separated off, and the aqueous phaseis extracted with dichloromethane. The combined organic phases arewashed with 1 M hydrochloric acid, twice with 1 M sodium hydroxidesolution and with brine. Then the organic phase is dried over sodiumsulfate, the solvent is removed and the residue is recrystallized fromethanol.

Yield: 86.3 g (64% of theory) Mass spectrum (ESI⁺): m/z=325/327/329(Br+Cl) [M+H]⁺

EXAMPLE V

1-Bromo-4-chloro-3-(4-methoxy-benzyl)-benzene

A solution of 86.2 g(5-bromo-2-chloro-phenyl)-(4-methoxy-phenyl)-methanone and 101.5 mLtriethylsilane in 75 mL dichloromethane and 150 mL acetonitrile iscooled to 10° C. Then with stirring 50.8 mL of boron trifluorideetherate are added so that the temperature does not exceed 20° C. Thesolution is stirred for 14 h at ambient temperature, before another 9 mLtriethylsilane and 4.4 mL boron trifluoride etherate are added. Thesolution is stirred for a further 3 h period at 45-50° C. and thencooled to ambient temperature. A solution of 28 g potassium hydroxide in70 mL water is added and the resultant mixture is stirred for 2 h. Theorganic phase is separated and the aqueous phase is extracted anotherthree times with diisopropylether. The combined organic phases arewashed twice with 2 M potassium hydroxide solution and once with brineand then dried over sodium sulfate. After the solvent is evaporated, theresidue is washed with ethanol and dried at 60° C.

Yield: 50.0 g (61% of theory) Mass spectrum (ESI⁺): m/z=310/312/314(Br+Cl) [M+H]⁺

EXAMPLE VI

4-(5-bromo-2-chloro-benzyl)-phenol

A solution of 14.8 g 1-bromo-4-chloro-3-(4-methoxy-benzyl)-benzene in150 mL dichloromethane is cooled in an ice bath. 50 mL of a 1 M solutionof boron tribromide in dichloromethane are added and the resultingsolution is stirred for 2 h at ambient temperature. The solution is thencooled in an ice bath again and saturated aqueous potassium carbonatesolution is added dropwise. At ambient temperature the mixture isadjusted with aqueous 1 M hydrochloric acid to pH 1, the organic phaseis separated off and the aqueous phase is extracted three times withethyl acetate. The combined organic phases are dried over sodium sulfateand the solvent is removed completely.

Yield: 13.9 g (98% of theory) Mass spectrum (ESI⁻): m/z=295/297/299(Br+Cl) [M−H]⁻

EXAMPLE VII

[4-(5-Bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane

A solution of 13.9 g 4-(5-bromo-2-chloro-benzyl)-phenol in 140 mLdichloromethane is cooled in an ice bath. Then 7.54 gtert-butyldimethylsilyl chloride in 20 mL dichloromethane are addedfollowed by 9.8 mL triethylamine and 0.5 g 4-dimethylaminopyridine. Theresultant solution is stirred for 16 h at ambient temperature and thendiluted with 100 mL dichloromethane. The organic phase is washed twicewith aqueous 1 M hydrochloric acid and once with aqueous sodium hydrogencarbonate solution and then dried over sodium sulfate. After the solventis removed, the residue is filtered through silica gel(cyclohexane/ethyl acetate 100:1).

Yield: 16.8 g (87% of theory) Mass spectrum (EI): m/z=410/412/414(Br+Cl) [M]⁺

EXAMPLE VIII

1-Bromo-4-(1-methoxy-D-glucopyranos-1-yl)-2-(phenoxymethyl)-benzene

A 2 M solution of iPrMgCl in THF (11 mL) is added to dry LiCl (0.47 g)suspended in THF (11 mL). The mixture is stirred at room temperatureuntil all the LiCl is dissolved. This solution is added dropwise to asolution of 4-bromo-1-iodo-3-phenoxymethyl-benzene (8.0 g) intetrahydrofuran (40 mL) cooled to −60° C. in argon atmosphere. Thesolution is warmed to −40° C. and then2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (10.7 g, 90% pure)in tetrahydrofuran (5 mL) is added. The resulting solution is warmed to−5° C. in the cooling bath and stirred for another 30 min at thistemperature. Aqueous NH₄Cl solution is added and the resultant mixtureis extracted with ethyl acetate. The combined organic extracts are driedover sodium sulphate and the solvent is removed under reduced pressure.The residue is dissolved in methanol (80 mL) and treated withmethanesulfonic acid (0.6 mL). After stirring the reaction solution at35-40° C. overnight, the solution is neutralized with solid NaHCO₃ andthe methanol is removed under reduced pressure. The remainder is dilutedwith aqueous NaHCO₃ solution and the resulting mixture is extracted withethyl acetate. The combined extracts are dried over sodium sulphate andthe solvent is evaporated to yield the crude product that is submittedto reduction without further purification.

Yield: 7.8 g (93% of theory)

EXAMPLE IX

1-Bromo-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-(phenoxymethyl)-benzene

Boron trifluoride etherate (4.9 mL) is added to a solution of1-bromo-4-(1-methoxy-D-glucopyranos-1-yl)-2-(phenoxymethyl)-benzene (8.7g) and triethylsilane (9.1 mL) in dichloromethane (35 mL) andacetonitrile (50 mL) cooled to −20° C. at such a rate that thetemperature maintains below −10° C. The resultant solution is warmed to0° C. over a period of 1.5 h and then treated with aqueous sodiumhydrogen carbonate solution. The resulting mixture is stirred for 0.5 h,the organic solvent is removed and the residue is extracted with ethylacetate. The combined organic layers are dried over sodium sulphate andthe solvent is removed. The residue is taken up in dichloromethane (50mL) and pyridine (9.4 mL), acetic anhydride (9.3 mL) and4-dimethylaminopyridine (0.5 g) are added in succession to the solution.The solution is stirred for 1.5 h at ambient temperature and thendiluted with dichloromethane. This solution is washed twice with 1 Mhydrochloric acid and dried over sodium sulfate. After the solvent isremoved, the residue is recrystallized from ethanol to furnish theproduct as a colorless solid.

Yield: 6.78 g (60% of theory) Mass spectrum (ESI⁺): m/z=610/612 (Br)[M+NH₄]⁺

EXAMPLE X

2-(Phenoxymethyl)-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzonitrile

A flask charged with zinc cyanide (1.0 g), zinc (30 mg),Pd₂(dibenzylideneacetone)₃*CHCl₃ (141 mg) and tri-tert-butylphosphoniumtetrafluoroborate (111 mg) is flushed with argon. Then a solution of1-bromo-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-(phenoxymethyl)-benzene(5.4 g) in degassed NMP (12 mL) is added and the resulting mixture isstirred at room temperature for 18 h. After dilution with ethyl acetate,the mixture is filtered and the filtrate is washed with aqueous sodiumhydrogen carbonate solution. The organic phase is dried (sodiumsulphate) and the solvent is removed. The residue is recrystallized fromethanol.

Yield: 4.10 g (84% of theory) Mass spectrum (ESI⁺): m/z=557 [M+NH₄]⁺

The compound described above is also obtained according to the followingprocedure:

A flask charged with a stir bar,1-bromo-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-(phenoxymethyl)-benzene(14.7 g), copper cyanide (4.1 g), and NMP (100 mL) is heated at refluxtemperature for 8 h. After dilution with water (600 mL), the precipitateis separated, washed a few times with water and subsequently dissolvedin ethyl acetate (200 mL). The resultant solution is filtered through aplug of silica gel using ethyl acetate (300 mL) as the eluent. Thefiltrate is concentrated under reduced pressure and the residue isdissolved in dichloromethane (100 mL) to reacetylate the oxygen groupsdeprotected during the cyanation. Accordingly, pyridine (4 mL),4-dimethylaminopyridine (0.3 g) and acetic anhydride (4.4 mL) are addedin succession. The resulting solution is stirred at room temperature for1 h. Then, the reaction mixture is diluted with dichloromethane (50 mL)and washed thrice with 1 M aqueous hydrochloric acid, once with aqueoussodium hydrogen carbonate solution and once with water. The organicphase is dried (sodium sulphate) and the solvent is removed. The residueis recrystallized from ethanol.

Yield: 10.0 g (75% of theory)

EXAMPLE XI

2-Bromomethyl-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzonitrile

A 33% solution of hydrobromic acid in acetic acid (15 mL) is added to asolution of2-phenyloxymethyl-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzonitrile(0.71 g) and acetic anhydride (0.12 mL) in acetic acid (10 ml). Theresulting solution is stirred at 55° C. for 6 h and then cooled in anice-bath. The reaction mixture is neutralized with chilled aqueouspotassium carbonate solution, and the resultant mixture is extractedwith ethyl acetate. The combined organic extracts are dried over sodiumsulfate and the solvent is removed under reduced pressure. The residueis taken up in ethyl acetate/cyclohexane (1:5), and the precipitate isseparated by filtration and dried at 50° C. to give the pure product.

Yield: 0.52 g (75% of theory) Mass spectrum (ESI⁺): m/z=543/545 (Br)[M+NH₄]⁺

EXAMPLE XII

1-Chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene

A solution of 4.0 g[4-(5-Bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane in 42mL dry diethyl ether is cooled to −80° C. under argon. 11.6 mL of achilled (ca. −50° C.) 1.7 M solution of tert-butyllithium in pentane areslowly added to the cooled solution and then the solution is stirred for30 min at −80° C. This solution is then added dropwise through atransfer needle, which is cooled with dry ice, to a solution of 4.78 g2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 38 mL diethylether chilled to −80° C. The resulting solution is stirred for 3 h at−78° C. Then a solution of 1.1 mL methanesulfonic acid in 35 mL methanolis added and the resultant reaction solution is stirred for another 16 hat ambient temperature. The solution is then neutralized with solidsodium hydrogen carbonate, ethyl acetate is added and the resultantsolution is concentrated under reduced pressure. Aqueous sodium hydrogencarbonate solution is added to the remaining solution that is extractedfour times with ethyl acetate. The combined organic phases are driedover sodium sulfate and the solvent is evaporated. The residue isdissolved in 30 mL acetonitrile and 30 mL dichloromethane and theresulting solution is cooled to −10° C. After the addition of 4.4 mLtriethylsilane, 2.6 mL boron trifluoride etherate are added dropwise sothat the temperature does not exceed −5° C. After the addition iscomplete, the reaction solution is stirred for another 5 h at −5 to −10°C. and then quenched by the addition of aqueous sodium hydrogencarbonate solution. The organic phase is separated and the aqueous phaseis extracted four times with ethyl acetate. The combined organic phasesare dried over sodium sulfate, the solvent is removed and the residue ispurified by chromatography on silica gel (dichloromethane/methanol). Theproduct then obtained is a mixture of isomers which can be separated byglobal acetylation of the hydroxyl groups with acetic anhydride,pyridine and 4-dimethylaminopyridine in dichloromethane andrecrystallisation of the resulting acetylated product from ethanol. Thepure acetylated β-product (precipitates from the ethanol solution) thusobtained is converted into the title compound by removal of the acetylgroups in methanol with 4 M potassium hydroxide solution.

Yield: 1.6 g (46% of theory) Mass spectrum (ESI⁺): m/z=398/400 (Cl)[M+NH₄]⁺

EXAMPLE XIII

1-Chloro-2-(4-cyclopentyloxybenzyl)-4-(β-D-glucopyranos-1-yl)-benzene

0.16 mL Iodocyclopentane are added to a mixture of 0.25 g1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene and 0.4 gcaesium carbonate in 2.5 mL of dimethylformamide. The mixture is stirredfor 4 h at 45° C., before another 0.1 g caesium carbonate and 0.05 mliodocyclopentane are added. After another 14 h stirring at 45° C.aqueous sodium chloride solution is added and the resulting mixture isextracted with ethyl acetate. The organic phase is dried over sodiumsulfate, the solvent is removed and the residue is purified using silicagel (dichloromethane/methanol 1:0->5:1).

Yield: 0.23 g (78% of theory) Mass spectrum (ESI⁺): m/z=466/468 (Cl)[M+NH₄]⁺

The following compound is obtained analogously to Example XIII:

(1)1-Chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene

The reaction is carried out withtetrahydrofuran-3-yl(R)-toluene-4-sulfonate as the coupling partner.

Mass spectrum (ESI⁺): m/z=451/453 (Cl) [M+H]⁺

EXAMPLE XIV

1-Chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(trifluoromethylsulfonyloxy)-benzyl]-benzene

10 mg 4-dimethylaminopyridine are added to a solution of 0.38 g1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene, 0.21 mltriethylamine and 0.39 g N,N-bis-(trifluoromethanesulfonyl)-aniline in10 ml dry dichloromethane. The solution is stirred for 4 h at ambienttemperature and then combined with brine. The resulting mixture isextracted with ethyl acetate, the organic extracts are dried over sodiumsulfate, and the solvent is removed. The residue is purified bychromatography on silica gel (dichloromethane/methanol 1:0->4:1).

Yield: 0.33 g (64% of theory) Mass spectrum (ESI⁺): m/z=530/532 (Cl)[M+NH₄]⁺

The following compound is obtained analogously to Example XIV:

(1)1-Cyano-4-(β-D-glucopyranos-1-yl)-2-[4-(trifluoromethylsulfonyloxy)-benzyl]-benzene

Mass spectrum (ESI⁺): m/z=504 [M+H]⁺

EXAMPLE XV

1-Chloro-4-(2,3,4,6-tetra-O-acetyl-R-D-glucopyranos-1-yl)-2-[4-(trifluoromethylsulfonyloxy)-benzyl]-benzene

To a solution of 5.6 g1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(trifluoromethylsulfonyloxy)-benzyl]-benzenein 75 mL dichloromethane is added consecutively 7 mL pyridine, 7.8 mLacetic anhydride and 0.12 g 4-dimethylaminopyridine. The solution isstirred at ambient temperature for 1 h. After adding 50 mL of water, theresultant mixture is stirred for another 5 min. The organic phase isseparated and washed with aqueous 1 M hydrochloric acid and aqueoussodium hydrogen carbonate solution. After drying over magnesium sulfateand evaporation of the organic solvent, the product is yielded as whitesolid.

Yield: 7.0 g (94% of theory) Mass spectrum (ESI⁺): m/z=698/700 (Cl)[M+NH₄]⁺

The following compound is obtained analogously to Example XV:

(1)1-Cyano-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-[4-(trifluoromethylsulfonyloxy)-benzyl]-benzene

Mass spectrum (ESI⁺): m/z=689 [M+NH₄]⁺

EXAMPLE XVI

1-Chloro-2-(4-ethynyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene

25 mg of copper iodide, 44 mg of bis-(triphenylphosphine)-palladiumdichloride, 0.30 ml triethylamine and finally 0.14 ml oftrimethylsilylacetylene are added under argon to a solution of 0.32 g1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(trifluoromethylsulphonyloxy)-benzyl]-benzenein 3 ml of dimethylformamide. The flask is tightly sealed and themixture is stirred for 8 h at 90° C. Then another 25 mg ofbis-(triphenylphosphine)-palladium dichloride and 0.1 mltrimethylsilylacetylene are added, and the solution is stirred for afurther 10 h at 90° C. Then aqueous sodium hydrogen carbonate solutionis added, the resultant mixture is extracted three times with ethylacetate, and the combined organic phases are dried over sodium sulfate.After the solvent has been evaporated, the residue is dissolved in 5 mlof methanol and combined with 0.12 g potassium carbonate. The mixture isstirred for 1 h at ambient temperature and then neutralised with 1 Mhydrochloric acid. Then the methanol is evaporated off, the residue iscombined with brine and extracted with ethyl acetate. The organicextracts collected are dried over sodium sulfate, and the solvent isremoved. The residue is purified by chromatography on silica gel(dichloromethane/methanol 1:0->5:1).

Yield: 0.095 g (40% of theory) Mass spectrum (ESI⁺): m/z=406/408 (Cl)[M+NH₄]⁺

EXAMPLE XVII

1-Chloro-2-(4-ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene

2.87 g 1-chloro-2-(4-ethynyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzeneare dissolved in 10 ml of ethyl acetate and 5 ml of ethanol. 0.3 g 10%palladium on carbon are added and the resultant mixture is stirred underhydrogen atmosphere (1 atm) overnight. The reaction mixture is filteredover Celite and the filtrate is concentrated. The residue is purified bychromatography on silica gel (dichloromethane/methanol 1:0->5:1).

Yield: 1.0 g (34% of theory) Mass spectrum (ESI⁺): m/z=410/412 (Cl)[M+NH₄]⁺

EXAMPLE XVIII

1-Chloro-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(2,3,4,6-tetra-O-acetyl-(β-D-glucopyranos-1-yl)-benzene

To a solution of 2.02 g1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzenein 20 mL dichloromethane is added in succession 2.5 mL pyridine, 2.8 mLacetic anhydride and 50 mg 4-dimethylaminopyridine. The reactionsolution is stirred at ambient temperature for 4 h. The solution isdiluted with 50 mL dichloromethane, washed twice with 50 mL 1 Mhydrochloric acid and once with sodium hydrogencarbonate solution. Afterdrying over sodium sulfate, the solvent is evaporated to yield theproduct.

Yield: 2.53 g (91% of theory) Mass spectrum (ESI⁺): m/z=642/644 (Cl)[M+Na]⁺

The following compounds are obtained analogously to Example XVIII:

(1)1-Chloro-2-(4-ethyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzene

(2)2-(4-Acetoxy-benzyl)-1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzene

Mass spectrum (ESI⁺): m/z=608/610 (CI) [M+NH₄]⁺

(3)1-Cyano-2-(4-methoxy-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzene

Mass spectrum (ESI⁺): m/z=576 [M+Na]⁺

EXAMPLE XIX

1-Chloro-2-(4-methyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-R-D-glucopyranos-1-yl)-benzene

Diisobutylaluminumhydride (54 μL, 1 mol/l in toluene) is added to amixture of 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II)(22 mg) in THF (3 mL) in Ar atmosphere and chilled in an ice-bath. Themixture is stirred in the ice-bath for 0.5 h and then1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-[4-(trifluoromethylsulfonyloxy)-benzyl]-benzene(0.60 g) and Me₂Zn (0.88 mL, 1 mol/L in toluene) are added insuccession. The ice-bath is removed and the mixture is heated at refluxfor 2.5 h. After cooling to room temperature, 1 M hydrochloric acid isadded and the resulting mixture is extracted with ethyl acetate. Theextracts collected are dried over sodium sulfate, and the solvent isremoved. The residue is purified by chromatography on silica gel(cyclohexane/ethyl acetate 1:0->2:1).

Yield: 0.25 g (52% of theory)

EXAMPLE XX

1-Chloro-2-(4-cyano-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzene

Tetrakis(triphenylphosphine)palladium(0) (0.13 g) is added to a flaskcharged with1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-[4-(trifluoromethylsulfonyloxy)-benzyl]-benzene(0.80 g) and zinc cyanide (0.14 g) in Ar atmosphere. The mixture isstirred at 100° C. for 3 h. After cooling to room temperature, ethylacetate is added and the resulting mixture is filtered, washed withaqueous NaHCO₃ solution, dried (sodium sulphate) and the solvent isremoved. The residue is recrystallized from ethanol.

Yield: 0.45 g (69% of theory) Mass spectrum (ESI⁺): m/z=580/582 (Cl)[M+Na]⁺

EXAMPLE XXI

4-Cyclopropyl-phenyl boronic acid

2.5 M nButyllithium in hexane (14.5 mL) is added dropwise to1-bromo-4-cyclopropyl-benzene (5.92 g) in THF (14 mL) and toluene (50mL) chilled to −70° C. The resultant solution is stirred at −70° C. for30 min before triisopropyl borate (8.5 mL) is added. The solution iswarmed to −20° C. and then treated with 4 M aqueous hydrochloric acid(15.5 mL). The reaction mixture is further warmed to room temperatureand then the organic phase is separated. The aqueous phase is extractedwith ethyl acetate and the combined organic phases are dried (sodiumsulphate). The solvent is evaporated and the residue is washed with amixture of ether and cyclohexane to give the product as a colorlesssolid.

Yield: 2.92 g (60% of theory) Mass spectrum (ESI⁻): m/z=207 (Cl)[M+HCOO]⁻

The following compounds are obtained analogously to Example XXI:

(1) 4-Difluoromethoxy-phenylboronic acid

Mass spectrum (ESI⁻): m/z=233 (Cl) [M+HCOO]⁻

In a departure from the procedure described above the compound isprepared from 4-difluoromethoxy-1-iodo-benzene using iPrMgCl to generatethe arylmetal compound and trapping this intermediate with trimethylborate.

(2) 4-Difluoromethyl-phenylboronic acid

Mass spectrum (ESI⁺): m/z=172 (Cl) [M+H]+

In a departure from the procedure described above the compound isprepared from 4-difluoromethyl-1-iodo-benzene (prepared from4-iodobenzaldehyde using diethylaminosulfurtrifluoride (DAST) indichloromethane) using iPrMgCl to generate the arylmetal compound andtrapping this intermediate with trimethyl borate.

EXAMPLE XXII

1-Bromo-4-cyano-3-(4-methoxy-benzyl)-benzene

A mixture of 25 g of ethyl(4-methoxy-phenyl)-acetate, 27.4 g of1-bromo-4-cyano-3-fluoro-benzene and 20 mL of N-methyl-pyrrolidin-2-oneis slowly added to 31.4 g of potassium tert butoxide in 130 mL ofN-methyl-pyrrolidin-2-one keeping the temperature below 10° C. Afterstirring for 1 hour at room temperature, 100 mL of methanol and 137 mLof 1M aqueous sodium hydroxide are added and the mixture is stirredovernight at room temperature. The methanol fraction is evaporated, theresidue is basified with 1M aqueous sodium hydroxide and extracted withtert butyl-methyl ether. The aqueous phase is acidified with 4 Mhydrochloric acid and extracted with ethyl acetate several times. Thecombined ethyl acetate extracts are evaporated and the residue togetherwith 120 mL of N,N-dimethyl formamide and 24.9 g of potassium carbonateheated at 100° C. for 1 hour. The reaction mixture is diluted withaqueous sodium bicarbonate and extracted several times with ethylacetate. The combined extracts are evaporated and the residuecrystallized from methanol.

Yield: 13 g (33% of theory) Mass spectrum (ESI⁺): m/z=319/321 (Br)[M+NH₄]⁺

The following compound is obtained analogously to Example XXII:

(1) 1-Bromo-4-cyano-3-(4-cyclopropyl-benzyl)-benzene

Mass spectrum (ESI⁻): m/z=329/331 (Br) [M+NH₄]⁺

The phenylacetic acid derivative needed for the preparation of thiscompound is synthesized according to the subsequent procedure ExampleXXIII.

EXAMPLE XXIII

Ethyl 4-cyclopropyl-phenylacetate

Prepared from Ethyl 4-bromo-phenylacetate by transition metal catalyzedcoupling with cyclopropylboronic acid using tricyclohexylphosphoniumtetrafluoroborate, palladium acetate, potassium phosphate in toluene andwater according to Tetrahedron Lett. 2002, 43, 6987-6990.

Mass spectrum (ESI⁺): m/z=205 [M+H]⁺

EXAMPLE XXIV

1-Cyano-4-(β-D-glucopyranos-1-yl)-2-(4-methoxybenzyl)-benzene

A flask charged with a stir bar and1-bromo-4-cyano-3-(4-methoxy-benzyl)-benzene (9.90 g) dissolved in dryTHF (120 mL) and kept under argon atmosphere is cooled to −87° C. Aprecooled (ca. −70° C.) solution of tert-butyllithium in pentane (1.7 M,39 mL) is slowly added to this solution and the resulting solution isstirred for 30 min at −87° C. Then, a solution of2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (16.5 g) dissolvedin THF (80 mL) is added and the combined solution is stirred at −75° C.for 1 h. The reaction is quenched with aqueous NH₄Cl solution and theresulting mixture is extracted with ethyl acetate. After drying (Na₂SO₄)of the organic extracts and removal of the solvent, the residue isdissolved in methanol (150 mL) and methanesulfonic acid (5 mL) is added.The resulting solution is stirred at 55° C. for 8 h to deliver thedesired anomeric configuration. After cooling to ambient temperature,the solution is neutralized with solid sodium hydrogen carbonate and themethanol is evaporated under reduced pressure. Brine is added to theremainder and the resulting mixture is extracted with ethyl acetate. Thecombined extracts are dried (sodium sulphate) and the solvent isevaporated. The residue is dissolved in acetonitrile (50 mL) anddichloromethane (50 mL) to reduce the anomeric carbon center. Aftercooling this solution to −20° C. and the addition of triethylsilane (16mL), boron trifluoride diethyletherate (9.2 mL) is added dropwise. Thereaction solution is slowly warmed in the cooling bath to 0° C. and thereaction is then quenched by the addition of aqueous sodium hydrogencarbonate solution. The organic phase is separated and the aqueous phaseis extracted with ethyl acetate. The combined organic phases are dried(sodium sulphate), the solvent is removed and the residue is purified bychromatography on silica gel (dichloromethane/methanol 1:0->9:1).

Yield: 5.2 g (41% of theory) Mass spectrum (ESI⁺): m/z=403 [M+NH₄]⁺

The following compound is obtained analogously to Example XXIV:

(1) 1-Cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene

Mass spectrum (ESI⁻): m/z=413 [M+H]⁺

Advantageously, the reduction of the anomeric carbon center of theappropriate intermediate obtained during the synthesis of this compoundis conducted with the oxygen functionalities on the pyranose ringprotected. Preferred protective groups are benzyl, p-methoxybenzyl,trimethylsilyl, triethylsilyl, tertbutyldimethylsilyl, triisopropylsilyland allyl.

EXAMPLE XXV

1-Cyano-2-(4-cyclopropyl-benzyl)-4-(tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzene

To a flask charged with a stir bar,4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-(4-trifluoromethylsulfonyloxy-benzyl)-benzonitrile(4.4 g), degassed toluene (12 mL) and degassed water (8 mL) and keptunder argon atmosphere is added cyclopropylboronic acid (0.20 g),potassium phosphate (5.0 g), tricyclohexylphosphine (0.19 g) and at lastpalladium(II) acetate (76 mg). The mixture is stirred at 110° C. for 6 hmeanwhile cyclopropylboronic acid is added after each hour (5×0.20 g).After cooling to room temperature, the mixture is diluted with aqueoussodium hydrogen carbonate solution and extracted with ethyl acetate. Thecombined extracts are dried (sodium sulphate) and the solvent is removedunder reduced pressure. The residue is chromatographed on silica gel(cyclohexane/ethyl acetate 20:1->1:1).

Yield: 3.2 g (87% of theory) Mass spectrum (ESI⁺): m/z=581 [M+NH₄]⁺

EXAMPLE XXVI

4-(1-Hydroxy-cyclopropyl)-phenylboronic acid

A 3.0 M solution of ethylmagnesium bromide in diethylether (7.6 mL) isadded to a stirred solution of titanium(IV) isopropoxide (2.2 mL) indiethylether (70 mL) chilled to −78° C. The resultant solution isstirred at −78° C. for 1.5 h, before 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.0 g) is added. The reactionmixture is warmed to ambient temperature and stirred for an additional12 h. Then, 1 M aqueous hydrochloric acid is added and the resultingmixture is extracted with ethyl acetate. The combined organic extractsare dried (sodium sulphate) and the solvent is evaporated. The residueis dissolved in acetone (60 mL) and 0.1 M aqueous NH₄OAc solution (50mL) followed by NalO₄ (2.3 g) is added. The resulting reaction mixtureis stirred at room temperature for 18 h. After removal of the acetone,the residue is extracted with ethyl acetate. The combined extracts aredried (sodium sulphate) and the solvent is evaporated. The residue ispurified by chromatography on silicagel (cyclohexane/ethyl acetate).

Yield: 0.45 g (33% of theory) Mass spectrum (ESI⁻): m/z=223 [M+HCOO]⁻

Preparation of the End Compounds:

REFERENCE EXAMPLE 1

4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuranyl-3-oxy)-benzyl]-benzonitrile

A mixture of 1.00 g1-chloro-2-[4-((S)-tetrahydrofuranyl-3-oxy)-benzyl]-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzene,0.16 sodium cyanide and 0.35 g nickel bromide in 2.5 mLN-methyl-2-pyrrolidinone is heated in a microwave oven at 220° C. for 15min. After cooling to room temperature, water is added and the resultantmixture is extracted with ethyl acetate. After drying over sodiumsulfate and evaporation of the solvent, the residue is dissolved in 5 mLmethanol. 4 mL of 4 M aqueous potassium hydroxide solution is added andthe reaction solution is stirred at ambient temperature for 3 h. Thesolution is neutralized with 1 M hydrochloric acid and the methanol isevaporated. The residue is extracted with ethylacetate, the combinedextracts are dried over sodium sulfate and the solvent is removed underreduced pressure. The residue is purified by chromatography on silicagel (dichloromethane/methanol 4:1).

Yield: 0.35 g (49% of theory) Mass spectrum (ESI⁺): m/z=442 [M+H]⁺

The compounds of the examples 1, 2, 3 and 4 are obtained analogously toReference Example 1:

EXAMPLE 1 2-(4-Ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile

Yield: 65% of theory Mass spectrum (ESI⁺): m/z=401 [M+NH₄]+

This compound may also be prepared analogously to Example 6 using4-ethylphenylboronic acid as the coupling partner.

EXAMPLE 2 4-(β-D-glucopyranos-1-yl)-2-(4-hydroxy-benzyl)-benzonitrile

The compound is prepared from2-(4-acetoxy-benzyl)-1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzeneaccording to the procedure described above

Yield: 30% of theory Mass spectrum (ESI⁺): m/z=389 [M+NH₄]⁺

The compound is also obtained by peracetylation of2-(4-methoxy-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile followed byether cleavage with boron tribromide and deacetylation.

EXAMPLE 3 4-(β-D-glucopyranos-1-yl)-2-(4-methyl-benzyl)-benzonitrile

Yield: 59% of theory Mass spectrum (ESI⁺): m/z=387 [M+NH₄]⁺

This compound may also be prepared analogously to Example 6 using4-methylphenylboronic acid as the coupling partner.

EXAMPLE 4 2-(4-Cyano-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile

Yield: 58% of theory Mass spectrum (ESI⁺): m/z=398 [M+NH₄]⁺

EXAMPLE 5

4-(β-D-glucopyranos-1-yl)-2-(4-methoxyethoxy-benzyl)-benzonitrile

2-Bromoethyl methyl ether (85 μl) is added to a mixture of4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzonitrile (0.30 g) andcesium carbonate (0.39 g) in 3 mL of dimethylformamide. The mixture isstirred at 80° C. for 16 h, before water and brine are added. Theresulting mixture is extracted with ethyl acetate, the combined extractsare dried over sodium sulphate and the solvent is removed under reducedpressure. The residue is purified by chromatography on silica gel(dichloromethane/methanol 1:0->5:1).

Yield: 0.19 g (49% of theory) Mass spectrum (ESI⁺): m/z=430 [M+H]+

EXAMPLE 6

4-(β-D-glucopyranos-1-yl)-2-(4-trifluoromethoxy-benzyl)-benzonitrile

An Ar filled flask is charged with2-bromomethyl-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzonitrile(0.25 g), 4-trifluoromethoxy-phenylboronic acid (0.20 g), potassiumcarbonate (0.26) and a 3:1 mixture of degassed acetone and water (4 mL).The mixture is stirred at room temperature for 5 min, before it iscooled in an ice-bath. Then palladium dichloride (5 mg) is added and thereaction mixture is stirred for 16 h at ambient temperature. The mixtureis then diluted with brine and extracted with ethyl acetate. Thecombined extracts are dried over sodium sulfate and the solvent isremoved under reduced pressure. The residue is dissolved in methanol (9mL) and treated with 4 M aqueous potassium hydroxide solution (1 mL).The resulting solution is stirred at ambient temperature for 1 h andthen neutralized with 1 M hydrochloric acid. The methanol is evaporated,and the residue is diluted with brine and extracted with ethyl acetate.The organic extracts collected are dried over sodium sulfate, and thesolvent is removed. The residue is chromatographed on silica gel(dichloromethane/methanol 1:0->8:1).

Yield: 0.145 g (69% of theory) Mass spectrum (ESI⁺): m/z=457 [M+NH₄]⁺

In some cases the yield is enhanced by employing 1.5 to 2.0 equivalentsof boronic acid along with the proportional rise of base.

The following compounds are obtained analogously to Example 6:

EXAMPLE 74-(β-D-glucopyranos-1-yl)-2-(4-trifluoromethyl-benzyl)-benzonitrile

Yield: 47% of theory Mass spectrum (ESI⁺): m/z=441 [M+NH₄]⁺

EXAMPLE 8 4-(β-D-glucopyranos-1-yl)-2-(4-isopropyl-benzyl)-benzonitrile

Yield: 87% of theory Mass spectrum (ESI⁺): m/z=415 [M+NH₄]⁺

EXAMPLE 9 4-(β-D-glucopyranos-1-yl)-2-(4-tert-butyl-benzyl)-benzonitrile

Yield: 66% of theory Mass spectrum (ESI⁺): m/z=429 [M+NH₄]⁺

EXAMPLE 104-(β-D-glucopyranos-1-yl)-2-(4-trimethylsilyl-benzyl)-benzonitrile

Yield: 70% of theory Mass spectrum (ESI⁺): m/z=445 [M+NH₄]⁺

EXAMPLE 114-(β-D-glucopyranos-1-yl)-2-(4-methylsulfanyl-benzyl)-benzonitrile

Yield: 47% of theory Mass spectrum (ESI⁺): m/z=419 [M+NH₄]⁺

EXAMPLE 124-(β-D-glucopyranos-1-yl)-2-[4-(3-methyl-but-1-yl)-benzyl]-benzonitrile

Yield: 69% of theory Mass spectrum (ESI⁺): m/z=443 [M+NH₄]⁺

EXAMPLE 13 2-(4-Fluoro-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile

Yield: 34% of theory Mass spectrum (ESI⁺): m/z=391 [M+NH₄]⁺

EXAMPLE 14 2-(4-Chloro-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile

Yield: 32% of theory Mass spectrum (ESI⁺): m/z=407/409 (Cl) [M+NH₄]⁺

EXAMPLE 152-(4-Difluoromethoxy-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile

Yield: 32% of theory Mass spectrum (ESI⁺): m/z=439 [M+NH₄]⁺

EXAMPLE 162-(4-Difluoromethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile

Yield: 65% of theory Mass spectrum (ESI⁺): m/z=423 [M+NH₄]⁺

EXAMPLE 172-(4-Cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile

Mass spectrum (ESI⁺): m/z=413 [M+NH₄]⁺

The compound is obtained according to example 6 using4-cyclopropyl-phenylboronic acid as the coupling partner.

Yield: 83% of theory

Alternatively this compound is obtained as described in Example XXIV(1).

The compound of example 17 is also obtained by employing the followingprocedure:

A solution of2-(4-cyclopropyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzonitrile(0.80 g) in methanol (5 mL) and THF (5 mL) is treated with aqueouspotassium hydroxide solution (4 mol/l, 5 mL). The reaction solution isstirred at ambient temperature for 1 h and then neutralized with 1 Mhydrochloric acid. The organic solvents are evaporated and the residueis diluted with brine and extracted with ethyl acetate. The organicextracts are dried (sodium sulphate) and the solvent is removed. Theresidue is chromatographed on silica gel (dichloromethane/methanol1:0->9:1).

Yield: 0.54 g (96% of theory)

EXAMPLE 182-(4-Cyclobutyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile

The compound is obtained according to example 6 using4-cyclobutylboronic acid (obtainable in analogy to example XXI) as thecoupling partner.

Yield: 51% of theory Mass spectrum (ESI⁺): m/z=427 [M+NH₄]⁺

EXAMPLE 19 4-(β-D-glucopyranos-1-yl)-2-(4-prop-1-yl-benzyl)-benzonitrile

Yield: 64% of theory Mass spectrum (ESI⁺): m/z=415 [M+NH₄]⁺

EXAMPLE 204-(β-D-glucopyranos-1-yl)-2-[4-(1-hydroxy-cyclopropyl)-benzyl]-benzonitrile

The compound may be obtained according to example 6 using4-(1-hydroxy-cyclopropyl)-phenylboronic acid as the coupling partner.

EXAMPLE 21

4-(β-D-glucopyranos-1-yl)-2-(4-iodo-benzyl)-benzonitrile

A 1 M solution of iodine monochloride in dichloromethane (0.9 mL) isadded to4-(β-D-glucopyranos-1-yl)-2-(4-trimethylsilyl-benzyl)-benzonitrile (0.26g) dissolved in dichloromethane (5 mL). The solution is stirred at roomtemperature for 1 h and then quenched by the addition of aqueous Na₂S₂O₃solution and aqueous NaHCO₃ solution. The organic phase is separated andthe aqueous phase is extracted with ethyl acetate. The combined organicphases are dried over sodium sulfate and the solvent is removed. Theresidue is chromatographed on silica gel (dichloromethane/methanol1:0->8:1).

Yield: 0.15 g (88% of theory) Mass spectrum (ESI⁺): m/z=499 [M+NH₄]+

The following compounds may be obtained analogously to Example 20:

(22) 2-(4-Bromo-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile

Yield: 79% of theory Mass spectrum (ESI⁺): m/z=451/453 [M+NH₄]⁺

The compound is obtained according to the procedure of Example 20 usingbromine instead of ICI in dichloromethane.

EXAMPLE 23

4-(β-D-glucopyranos-1-yl)-2-(4-pentafluoroethyl-benzyl)-benzonitrile

A flask charged with4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4-iodo-benzyl)-benzonitrile(0.16 g), pentafluoroethyltrimethylsilane (0.14 g), KF (43 mg), CuI(0.16 g), DMF (2 mL) and Ar atmosphere is heated at 60° C. for 24 h.Then, aqueous NaHCO₃ solution is added and the resulting mixture isextracted with ethyl acetate. The combined organic phases are dried oversodium sulfate and the solvent is removed. The residue is dissolved inmethanol (8 mL) and treated with 4 M KOH solution (0.8 mL). The solutionis stirred at room temperature for 1 h and then diluted with aqueousNaHCO₃ solution. After removal of the methanol under reduced pressure,the residue is extracted with ethyl acetate, the combined organicextracts are dried and the solvent is removed. The residue ischromatographed on silica gel (dichloromethane/methanol 1:0->8:1).

Yield: 0.08 g (69% of theory) Mass spectrum (ESI⁺): m/z=491 [M+NH₄]+

EXAMPLE 24

4-(β-D-glucopyranos-1-yl)-2-(4-methylsulfinyl-benzyl)-benzonitrile

35% Hydrogen peroxide in water (48 μL) is added to4-(1-D-glucopyranos-1-yl)-2-(4-methylsulfanyl-benzyl)-benzonitrile (83mg) in 1,1,1,3,3,3-hexafluoroisopropanol (2 mL). The resulting solutionis stirred at ambient temperature for 1 h and then quenched by theaddition of aqueous Na₂S₂O₃ solution and aqueous NaHCO₃ solution. Theorganic phase is separated and the aqueous phase is extracted with ethylacetate. The combined organic phases are dried over sodium sulfate andthe solvent is removed. The residue is chromatographed on silica gel(dichloromethane/methanol 1:0->5:1).

Yield: 24 mg (28% of theory) Mass spectrum (ESI⁺): m/z=418 [M+H]⁺

EXAMPLE 25

4-(β-D-glucopyranos-1-yl)-2-(4-methylsulfonyl-benzyl)-benzonitrile

3-Chloroperoxybenzoic acid (70%, 0.14 g) is added to4-(β-D-glucopyranos-1-yl)-2-(4-methylsulfanyl-benzyl)-benzonitrile (100mg) in dichloromethane (2 mL) chilled in an ice-bath. The cooling bathis removed and the resulting solution is stirred at ambient temperaturefor 1 h. After the addition of aqueous Na₂S₂O₃ solution and aqueousNaHCO₃ solution, the organic phase is separated and the aqueous phase isextracted with ethyl acetate. The combined organic phases are dried oversodium sulfate and the solvent is removed. The residue ischromatographed on silica gel (dichloromethane/methanol 1:0->8:1).

Yield: 68 mg (63% of theory) Mass spectrum (ESI⁺): m/z=451 [M+NH₄]⁺

The following compounds may also be prepared analogously to theabove-mentioned Examples or other methods known from the literature:

Ex. Structure 26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

Some examples of formulations will now be described in which the term“active substance” denotes one or more compounds according to theinvention, including the prodrugs or salts thereof. In the case of oneof the combinations with one or additional active substances asdescribed previously, the term “active substance” also includes theadditional active substances.

EXAMPLE A

Tablets Containing 100 mg of Active Substance

Composition:

1 tablet contains:

active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mgpolyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mgMethod of Preparation:

The active substance, lactose and starch are mixed together anduniformly moistened with an aqueous solution of thepolyvinylpyrrolidone. After the moist composition has been screened (2.0mm mesh size) and dried in a rack-type drier at 50° C. it is screenedagain (1.5 mm mesh size) and the lubricant is added. The finishedmixture is compressed to form tablets.

-   -   Weight of tablet: 220 mg    -   Diameter: 10 mm, biplanar, facetted on both sides and notched on        one side.

EXAMPLE B

Tablets Containing 150 mg of Active Substance

Composition:

1 tablet contains:

active substance 150.0 mg powdered lactose 89.0 mg corn starch 40.0 mgcolloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate1.0 mg 300.0 mgPreparation:

The active substance mixed with lactose, corn starch and silica ismoistened with a 20% aqueous polyvinylpyrrolidone solution and passedthrough a screen with a mesh size of 1.5 mm. The granules, dried at 45°C., are passed through the same screen again and mixed with thespecified amount of magnesium stearate. Tablets are pressed from themixture.

-   -   Weight of tablet: 300 mg    -   die: 10 mm, flat

EXAMPLE C

Hard Gelatine Capsules Containing 150 mg of Active Substance

Composition:

1 capsule contains:

active substance 150.0 mg corn starch (dried) approx. 180.0 mg lactose(powdered) approx.  87.0 mg magnesium stearate  3.0 mg approx. 420.0 mgPreparation:

The active substance is mixed with the excipients, passed through ascreen with a mesh size of 0.75 mm and homogeneously mixed using asuitable apparatus. The finished mixture is packed into size 1 hardgelatine capsules.

-   -   Capsule filling: approx. 320 mg    -   Capsule shell: size 1 hard gelatine capsule.

EXAMPLE D

Suppositories Containing 150 mg of Active Substance

Composition:

1 suppository contains:

active substance 150.0 mg polyethyleneglycol 1500 550.0 mgpolyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate840.0 mg 2,000.0 mgPreparation:

After the suppository mass has been melted the active substance ishomogeneously distributed therein and the melt is poured into chilledmoulds.

EXAMPLE E

Ampoules Containing 10 mg Active Substance

Composition:

active substance 10.0 mg 0.01N hydrochloric acid q.s. double-distilledwater ad 2.0 mlPreparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 2ml ampoules.

EXAMPLE F

Ampoules Containing 50 mg of Active Substance

Composition:

active substance 50.0 mg 0.01N hydrochloric acid q.s. double-distilledwater ad 10.0 mlPreparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 10ml ampoules.

1. A glucopyranosyl-substituted benzonitrile derivative of formula I

wherein R³ denotes hydrogen, fluorine, chlorine, bromine, iodine,methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl,tert-butyl, 3-methyl-but-1-yl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl,1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, difluoromethyl,trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl,3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl,3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl,2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl,2-ethoxy-ethyl, difluoromethyloxy, trifluoromethyloxy,2-methyloxy-ethyloxy, methylsulfinyl, methlysulfonyl, ethylsulfinyl,ethylsulfonyl, trimethylsilyl, or cyano; or a derivative thereof whereinone or more hydroxyl groups of the β-D-glucopyranosyl group are acylatedwith a group selected from (C₁₋₁₈-alkyl)carbonyl,(C₁₋₁₈-alkyl)oxycarbonyl, phenylcarbonyl andphenyl-(C₁₋₃-alkyl)-carbonyl.
 2. The glucopyranosyl-substitutedbenzonitrile derivative according to claim 1 characterized in that thehydrogen atom of the hydroxyl group O-6 of the β-D-glucopyranosyl-groupis replaced by a group selected from among (C₁₋₈-alkyl)carbonyl,(C₁₋₈-alkyl)oxycarbonyl and phenylcarbonyl.
 3. A pharmaceuticalcomposition, comprising a compound according to claim
 1. 4. Thepharmaceutical composition according to claim 3, further comprising oneor more inert carriers and/or diluents.
 5. A method of treating adisease or a condition which can be influenced by inhibiting thesodium-dependent glucose cotransporter SGLT said method comprised of thesteps of administering to a patient in need thereof a therapeuticallyeffective amount of a compound according to claim 1 wherein said adisease or a condition is selected from the group consisting of type 1and type 2 diabetes mellitus, complications of diabetes, metabolicacidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia, glucosemetabolic disorder, insulin resistance, metabolic syndrome,dyslipidaemias of different origins, atherosclerosis and relateddiseases, obesity, high blood pressure, chronic heart failure, oedema,and hyperuricaemia.
 6. A method of treating metabolic disorders, saidmethod comprised of the step of administering to a patient in needthereof a therapeutically effective amount of a compound according toclaim 1, wherein said-metabolic disorder is selected from the groupconsisting of type 1 and type 2 diabetes mellitus, complications ofdiabetes, metabolic acidosis or ketosis, reactive hypoglycaemia,hyperinsulinaemia, glucose metabolic disorder, insulin resistance,metabolic syndrome, dyslipidaemias of different origins, atherosclerosisand related diseases, obesity, high blood pressure, chronic heartfailure, oedema and hyperuricaemia.
 7. A method of inhibiting thesodium-dependent glucose cotransporter SGLT2, said method comprised ofthe step of administering to a patient in need thereof a therapeuticallyeffective amount of a compound according to claim
 1. 8. A method oftreating the degeneration of pancreatic beta cells and/or for improvingthe functionality of beta cells, said method comprised of the step ofadministering to a patient in need thereof a therapeutically effectiveamount of a compound according to claim
 1. 9. A method of slowing,delaying or treating diseases or conditions attributed to abnormalaccumulation of liver fat, said method comprised of the step ofadministering to a patient in need thereof a therapeutically effectiveamount of a compound according to claim
 1. 10. Aglucopyranosyl-substituted benzonitrile derivative of formula II, III,i.1, i.2, i.3, i.4, i.5, and i.6:

wherein R³ is defined as in claim 1 and R¹ denotes H, C₁₋₄-alkyl,(C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl oraryl-(C₁₋₃-alkyl)-carbonyl, wherein the alkyl or aryl groups may bemono- or polysubstituted by halogen; R^(8a), R^(8b), R^(8c), R^(8d)independently of one another denote hydrogen or an allyl group, a benzylgroup, a (C₁₋₄-alkyl)carbonyl, (C₁₋₄-alkyl)oxycarbonyl, arylcarbonyl,aryl-(C₁₋₃-alkyl)-carbonyl and aryl-(C₁₋₃-alkyl)-oxycarbonyl or aR^(a)R^(b)R^(c)Si group or a ketal or acetal group, particularly analkylidene or arylalkylidene ketal or acetal group, while in each casetwo adjacent groups R^(8a), R^(8b), R^(8c), R^(8d) may form a cyclicketal or acetal group or a1,2-di(C₁₋₃-alkoxy)-1,2-di(C₁₋₃-alkyl)-ethylene bridge, while theabove-mentioned ethylene bridge forms, together with two oxygen atomsand the two associated carbon atoms of the pyranose ring, a substituteddioxane ring, particularly a2,3-dimethyl-2,3-di(C₁₋₃-alkoxy)-1,4-dioxane ring, and while alkyl,allyl, aryl and/or benzyl groups may be mono- or polysubstituted byhalogen or C₁₋₃-alkoxy, and while benzyl groups may also be substitutedby a di-(C₁₋₃-alkyl)amino group; and R^(a), R^(b), R^(c) independentlyof one another denote C₁₋₄-alkyl, aryl or aryl-C₁₋₃-alkyl, wherein thearyl or alkyl groups may be mono- or polysubstituted by halogen; whileby the aryl groups mentioned in the definition above are meant phenyl ornaphthyl groups; and Alk denotes C₁₋₄-alkyl; and R¹ denotes chlorine,bromine, cyano, carboxy, carboxylic ester, carboxamide or a derivativethereof, a boron or silyl group, a protected or masked aldehyde group,or a protected or masked amino group; and LG denotes a leaving group;and U denotes Cl, Br, I, —O—CO—C₁₋₄-alkyl, —O—C(═O)—O—C₁₋₄-alkyl, or—OPO(O—C₁₋₄-alkyl).
 11. A glucopyranosyl-substituted benzonitrilederivative according to claim 1, wherein R³ denotes hydrogen, fluorine,chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl,1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl,difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl,hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl,3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl,2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl,2-ethoxy-ethyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl,ethylsulfonyl, trimethylsilyl, or cyano.
 12. Aglucopyranosyl-substituted benzonitrile derivative selected from thegroup consisting of:2-(4-Lthyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile;4-(β-D-glucopyranos-1-yl)-2-(4-methyl-benzyl)-benzonitrile;4-(β-D-glucopyranos-1-yl)-2-(4-trifluoromethoxy-benzyl)-benzonitrile;4-(β-D-glucopyranos-1-yl)-2-(4-methoxyethoxy-benzyl)-benzonitrile;4-(β-D-glucopyranos-1-yl)-2-(4-trifluoromethyl-benzyl)-benzonitrile;4-(β-D-glucopyranos-1-yl)-2-(4-isopropyl-benzyl)-benzonitrile;4-(β-D-glucopyranos-1-yl)-2-[4-(3-methyl-but-1-yl)-benzyl]-benzonitrile;2-(4-Difluoromethoxy-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile;2-(4-Difluoromethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile;2-(4-Cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile;2-(4-Cyclobutyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile;4-(β-D-glucopyranos-1-yl)-2-(4-prop-1-yl-benzyl)-benzonitrile;4-(β-D-glucopyranos-1-yl)-2-(4-iodo-benzyl)-benzonitrile;2-(4-Bromo-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile.
 13. Theglucopyranosyl-substituted benzonitrile derivative according to claim10, wherein the aryl groups are phenyl groups.
 14. Theglucopyranosyl-substituted benzonitrile derivative according to claim10, wherein R¹ Br or CN.
 15. The glucopyranosyl-substituted benzonitrilederivative according to claim 10, wherein LG is Br, I, or —O—(SO₂)—CF₃.